Yuyan Jiang

All Publications

• Gold-siRNA supraclusters enhance the anti-tumor immune response of stereotactic ablative radiotherapy at primary and metastatic tumors. Nature biotechnology Jiang, Y., Cao, H., Deng, H., Guan, L., Langthasa, J., Colburg, D. R., Melemenidis, S., Cotton, R. M., Aleman, J., Wang, X. J., Graves, E. E., Kalbasi, A., Pu, K., Rao, J., Le, Q. T. 2024

  Abstract

  Strategies to enhance the anti-tumor immune response of stereotactic ablative radiotherapy (SABR) at primary tumors and abscopal sites are under intensive investigation. Here we report a metabolizable binary supracluster (BSCgal) that combines gold nanoclusters as radiosensitizing adjuvants with small interfering RNA (siRNA) targeting the immunosuppressive mediator galectin-1 (Gal-1). BSCgal comprises reversibly crosslinked cationic gold nanoclusters and siRNA complexes in a polymer matrix that biodegrades over weeks, facilitating clearance (90.3% in vivo clearance at 4 weeks) to reduce toxicity. The particle size well above the renal filtration threshold facilitates passive delivery to tumors. Using mouse models of head and neck cancer, we show that BSCgal augments the radiodynamic and immunotherapeutic effects of SABR at the primary and metastatic tumors by promoting tumor-inhibitory leukocytes, upregulating cytotoxic granzyme B and reducing immunosuppressive cell populations. It outperforms SABR plus Gal-1 antagonists, chemoradiation drug cisplatin or PD-1 inhibitor. This work presents a translatable strategy to converge focal radiosensitization with targeted immune checkpoint silencing for personalized radioimmunotherapy.

  View details for DOI 10.1038/s41587-024-02448-0

  View details for PubMedID 39448881

  View details for PubMedCentralID 6053911

• Molecular Imaging of Renin Activity using Fluorogenic Nanoprobes for Precision Antihypertensive Therapy. Angewandte Chemie (International ed. in English) Zhou, Y., Xu, W., Ruan, B., Zhu, L., Jiang, Y., Cai, H., Huang, J. 2024: e202416002

  Abstract

  Life-threatening hypertension remains inadequately controlled in clinics due to its heterogenous renin levels. Rapid stratification of hypertension through renin analysis is crucial for effective personalized treatment, yet an ultrasensitive detection approach is currently lacking. Here, we report activatable renin nanoprobes (ARNs) for non-invasive and ultrasensitive profiling of renin activity and guiding antihypertensive treatment decision through near-infrared fluorescence (NIRF) in vivo imaging and in vitro urinalysis. ARNs are intrinsically non-fluorescent due to NIRF reporter connected to a gold nanocluster through a renin-responsive peptide. In hyperreninemia mouse models, ARNs specifically react with renin to liberate the renal clearable NIRF reporter for accurate renin detection that outperforms the gold standard radioimmunoassay. Such specific and sensitive detection also enables imaging-based high-throughput screening of antihypertensive drugs. In hypertensive rat models, ARNs enable ultrasensitive detection of both plasma and urinary renin, facilitating renin-guided precision treatment and significantly improving hypertension control rate (90% versus 58%). Our nanoprobe platform holds great potential for assisting clinicians in rapidly and accurately classifying hypertensive patients and improving outcomes through tailored treatment selection.

  View details for DOI 10.1002/anie.202416002

  View details for PubMedID 39279688

• Tert-expressing cells contribute to salivary gland homeostasis and tissue regeneration after radiation therapy. Genes & development Guan, L., Viswanathan, V., Jiang, Y., Vijayakumar, S., Cao, H., Zhao, J., Colburg, D. R., Neuhöfer, P., Zhang, Y., Wang, J., Xu, Y., Laseinde, E. E., Hildebrand, R., Rahman, M., Frock, R., Kong, C., Beachy, P. A., Artandi, S., Le, Q. T. 2024

  Abstract

  Salivary gland homeostasis and regeneration after radiotherapy depend significantly on progenitor cells. However, the lineage of submandibular gland (SMG) progenitor cells remains less defined compared with other normal organs. Here, using a mouse strain expressing regulated CreERT2 recombinase from the endogenous Tert locus, we identify a distinct telomerase-expressing (TertHigh) cell population located in the ductal region of the adult SMG. These TertHigh cells contribute to ductal cell generation during SMG homeostasis and to both ductal and acinar cell renewal 1 year after radiotherapy. TertHigh cells maintain self-renewal capacity during in vitro culture, exhibit resistance to radiation damage, and demonstrate enhanced proliferative activity after radiation exposure. Similarly, primary human SMG cells with high Tert expression display enhanced cell survival after radiotherapy, and CRISPR-activated Tert in human SMG spheres increases proliferation after radiation. RNA sequencing reveals upregulation of "cell cycling" and "oxidative stress response" pathways in TertHigh cells following radiation. Mechanistically, Tert appears to modulate cell survival through ROS levels in SMG spheres following radiation damage. Our findings highlight the significance of TertHigh cells in salivary gland biology, providing insights into their response to radiotherapy and into their use as a potential target for enhancing salivary gland regeneration after radiotherapy.

  View details for DOI 10.1101/gad.351577.124

  View details for PubMedID 38997156

• Molecular Engineering of Activatable NIR-II Hemicyanine Reporters for Early Diagnosis and Prognostic Assessment of Inflammatory Bowel Disease. ACS nano Liu, Y., Diao, S., Ruan, B., Zhou, Y., Yu, M., Dong, G., Xu, W., Ning, L., Zhou, W., Jiang, Y., Xie, C., Fan, Q., Huang, J. 2024; 18 (11): 8437-8451

  Abstract

  Molecular imaging in the second near-infrared window (NIR-II) provides high-fidelity visualization of biopathological events in deep tissue. However, most NIR-II probes produce "always-on" output and demonstrate poor signal specificity toward biomarkers. Herein, we report a series of hemicyanine reporters (HBCs) with tunable emission to NIR-II window (715-1188 nm) and structurally amenable to constructing activatable probes. Such manipulation of emission wavelengths relies on rational molecular engineering by integrating benz[c,d]indolium, benzo[b]xanthonium, and thiophene moieties to a conventional hemicyanine skeleton. In particular, HBC4 and HBC5 possess bright and record long emission over 1050 nm, enabling improved tissue penetration depth and superior signal to background ratio for intestinal tract mapping than NIR-I fluorophore HC1. An activatable inflammatory reporter (AIR-PE) is further constructed for pH-triggered site-specific release in colon. Due to minimized background interference, oral gavage of AIR-PE allows clear delineation of irritated intestines and assessment of therapeutic responses in a mouse model of inflammatory bowel disease (IBD) through real-time NIRF-II imaging. Benefiting from its high fecal clearance efficiency (>90%), AIR-PE can also detect IBD and evaluate the effectiveness of colitis treatments via in vitro optical fecalysis, which outperforms typical clinical assays including fecal occult blood testing and histological examination. This study thus presents NIR-II molecular scaffolds that are not only applicable to developing versatile activatable probes for early diagnosis and prognostic monitoring of deeply seated diseases but also hold promise for future clinical translations.

  View details for DOI 10.1021/acsnano.3c13105

  View details for PubMedID 38501308

• Size-Transformable Superoxide-Triggered Nanoreporters for Crosstalk-Free Dual Fluorescence/Chemiluminescence Imaging and Urinalysis in Living Mice. Angewandte Chemie (International ed. in English) Ruan, B., Yu, M., Zhou, Y., Xu, W., Liu, Y., Liu, B., Zhu, L., Yi, S., Jiang, Y., Huang, J. 2023: e202305812

  Abstract

  Chemiluminescence imaging has been recognized as a valuable tool for ultrasensitive detection of physio-pathological events through elimination of background autofluorescence. However, most chemiluminescent nanoprobes suffer from shallow imaging depths and slow clearance from living bodies, which impede their use in clinical settings. We herein report size-transformable nanoreporters (ADN1 and ADN2) that could be activated at disease site by superoxide anion (O2•-) to trigger nanostructure disassembly into renal excretable fluorescent fragments as well as chemiluminescence turn-on for crosstalk-free duplex chemo-fluorescence imaging and in vitro urinalysis. In peritonitis mouse model, we demonstrate that the representative nanoreporter ADN1 spontaneously accumulates at the disrupted peritoneum and is cleaved by upregulated O2•- to initiate depolymerization and result in red chemiluminescence at 620 nm, enabling sensitive detection of peritonitis at least 19 h earlier than gold standard histological assays. Additionally, the incorporation of a near-infrared (NIR) dye into ADN1 results in ADN2 exhibiting intense and red-shifted chemiluminescence at ~800 nm, which permits early detection of deeply seated diseases such as drug-induced hepatotoxicity. This study thus showcases a modular design strategy that is not only applicable to developing versatile chemiluminescent nanoprobes with switchable pharmacokinetics for early disease diagnosis, but also promising for future clinical translations.

  View details for DOI 10.1002/anie.202305812

  View details for PubMedID 37258940

• Light-driven Self-recruitment of Biomimetic Semiconducting Polymer Nanoparticles for Precise Tumor Vascular Disruption. Advanced materials (Deerfield Beach, Fla.) Li, H., Zhou, S., Wu, M., Qu, R., Wang, X., Chen, W., Jiang, Y., Jiang, X., Zhen, X. 2023: e2210920

  Abstract

  Tumor vascular disrupting therapy has offered promising opportunities to treat cancer in clinical practice, whereas the overall therapeutic efficacy is notably limited due to the off-target effects and repeated dose toxicity of vascular disrupting agents (VDAs). To tackle this problem, we herein report a VDA-free biomimetic semiconducting polymer nanoparticle (SPNP ) for precise tumor vascular disruption through two-stage light manipulation. SPNP consists of a semiconducting polymer nanoparticle as the photothermal agent camouflaged with platelet membranes that specifically target disrupted vasculature. Upon the first photoirradiation, SPNP administered in vivo generates mild hyperthermia to trigger tumor vascular hemorrhage, which activates the coagulation cascade and recruits more SPNP to injured blood vessels. Such enhanced tumor vascular targeting of photothermal agents enables intense hyperthermia to destroy the tumor vasculature during the second photoirradiation, leading to complete tumor eradication and efficient metastasis inhibition. Intriguingly, the mechanism study revealed that this vascular disruption strategy alleviates splenomegaly and reverses the immunosuppressive tumor microenvironment by reducing myeloid-derived suppressor cells. Therefore, this study not only illustrates a light-driven self-recruitment strategy to enhance tumor vascular disruption via a single dose of biomimetic therapeutics but also deciphers the immunotherapeutic role of vascular disruption therapy that is conducive to clinical studies. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/adma.202210920

  View details for PubMedID 36938865

• Nanoparticles with ultrasound-induced afterglow luminescence for tumour-specific theranostics. Nature biomedical engineering Xu, C., Huang, J., Jiang, Y., He, S., Zhang, C., Pu, K. 2023; 7 (3): 298-312

  Abstract

  Molecular imaging via afterglow luminescence minimizes tissue autofluorescence and increases the signal-to-noise ratio. However, the induction of afterglow requires the prior irradiation of light, which is attenuated by scattering and absorption in tissue. Here we report the development of organic nanoparticles producing ultrasound-induced afterglow, and their proof-of-concept application in cancer immunotheranostics. The 'sonoafterglow' nanoparticles comprise a sonosensitizer acting as an initiator to produce singlet oxygen and subsequently activate a substrate for the emission of afterglow luminescence, which is brighter and detectable at larger tissue depths (4 cm) than previously reported light-induced afterglow. We formulated sonoafterglow nanoparticles containing a singlet-oxygen-cleavable prodrug for the immune-response modifier imiquimod that specifically turn on in the presence of the inflammation biomarker peroxynitrite, which is overproduced by tumour-associated M1-like macrophages. Systemic delivery of the nanoparticles allowed for sonoafterglow-guided treatment of mice bearing subcutaneous breast cancer tumours. The high sensitivity and depth of molecular sonoafterglow imaging may offer advantages for the real-time in vivo monitoring of physiopathological processes.

  View details for DOI 10.1038/s41551-022-00978-z

  View details for PubMedID 36550302

  View details for PubMedCentralID 1201471

• Renal clearable polyfluorophore nanosensors for early diagnosis of cancer and allograft rejection. Nature materials Huang, J., Chen, X., Jiang, Y., Zhang, C., He, S., Wang, H., Pu, K. 2022; 21 (5): 598-607

  Abstract

  Optical nanoparticles are promising diagnostic tools; however, their shallow optical imaging depth and slow clearance from the body have impeded their use for in vivo disease detection. To address these limitations, we develop activatable polyfluorophore nanosensors with biomarker-triggered nanoparticle-to-molecule pharmacokinetic conversion and near-infrared fluorogenic turn-on response. Activatable polyfluorophore nanosensors can accumulate at the disease site and react with disease-associated proteases to undergo in situ enzyme-catalysed depolymerization. This disease-specific interaction liberates renal-clearable fluorogenic fragments from activatable polyfluorophore nanosensors for non-invasive longitudinal urinalysis and outperforms the gold standard blood and urine assays, providing a level of sensitivity and specificity comparable to those of invasive biopsy and flow cytometry analysis. In rodent models, activatable polyfluorophore nanosensors enable ultrasensitive detection of tumours (1.6 mm diameter) and early diagnosis of acute liver allograft rejection. We anticipate that our modular nanosensor platform may be applied for early diagnosis of a range of diseases via a simple urine test.

  View details for DOI 10.1038/s41563-022-01224-2

  View details for PubMedID 35422505

• Tether-free photothermal deep-brain stimulation in freely behaving mice via wide-field illumination in the near-infrared-II window. Nature biomedical engineering Wu, X., Jiang, Y., Rommelfanger, N. J., Yang, F., Zhou, Q., Yin, R., Liu, J., Cai, S., Ren, W., Shin, A., Ong, K. S., Pu, K., Hong, G. 2022

  Abstract

  Neural circuitry is typically modulated via invasive brain implants and tethered optical fibres in restrained animals. Here we show that wide-field illumination in the second near-infrared spectral window (NIR-II) enables implant-and-tether-free deep-brain stimulation in freely behaving mice with stereotactically injected macromolecular photothermal transducers activating neurons ectopically expressing the temperature-sensitive transient receptor potential cation channel subfamily V member 1 (TRPV1). The macromolecular transducers, ~40 nm in size and consisting of a semiconducting polymer core and an amphiphilic polymer shell, have a photothermal conversion efficiency of 71% at 1,064 nm, the wavelength at which light attenuation by brain tissue is minimized (within the 400-1,800 nm spectral window). TRPV1-expressing neurons in the hippocampus, motor cortex and ventral tegmental area of mice can be activated with minimal thermal damage on wide-field NIR-II illumination from a light source placed at distances higher than 50 cm above the animal's head and at an incident power density of 10 mW mm-2. Deep-brain stimulation via wide-field NIR-II illumination may open up opportunities for social behavioural studies in small animals.

  View details for DOI 10.1038/s41551-022-00862-w

  View details for PubMedID 35314800

• Molecular Probes for Autofluorescence-Free Optical Imaging. Chemical reviews Jiang, Y., Pu, K. 2021; 121 (21): 13086-13131

  Abstract

  Optical imaging is an indispensable tool in clinical diagnostics and fundamental biomedical research. Autofluorescence-free optical imaging, which eliminates real-time optical excitation to minimize background noise, enables clear visualization of biological architecture and physiopathological events deep within living subjects. Molecular probes especially developed for autofluorescence-free optical imaging have been proven to remarkably improve the imaging sensitivity, penetration depth, target specificity, and multiplexing capability. In this Review, we focus on the advancements of autofluorescence-free molecular probes through the lens of particular molecular or photophysical mechanisms that produce long-lasting luminescence after the cessation of light excitation. The versatile design strategies of these molecular probes are discussed along with a broad range of biological applications. Finally, challenges and perspectives are discussed to further advance the next-generation autofluorescence-free molecular probes for in vivo imaging and in vitro biosensors.

  View details for DOI 10.1021/acs.chemrev.1c00506

  View details for PubMedID 34558282

• Second Near-Infrared Light-Activatable Polymeric Nanoantagonist for Photothermal Immunometabolic Cancer Therapy. Advanced materials (Deerfield Beach, Fla.) Xu, C., Jiang, Y., Huang, J., Huang, J., Pu, K. 2021; 33 (36): e2101410

  Abstract

  Immunometabolic modulation offers new opportunities to treat cancers as it is highly associated with cancer progression and immunosuppressive microenvironment. However, traditional regimens using nonselective small-molecule immunomodulators lead to the off-target adverse effects and insufficient therapeutic outcomes. Herein a second near-infrared (NIR-II) photothermally activatable semiconducting polymeric nanoantagonist (ASPA) for synergistic photothermal immunometabolic therapy of cancer is reported. ASPA backbone is obtained by conjugating vipadenant, an antagonist to adenosine A2A receptor, onto NIR-II light-absorbing semiconducting polymer via an azo-based thermolabile linker. Under deep-penetrating NIR-II photoirradiation, ASPA induces tumor thermal ablation and subsequently immunogenic cell death, triggers the cleavage of thermolabile linker, and releases the antagonist to block the immunosuppressive adenosinergic pathway. Such a remotely controlled immunometabolic regulation potentiates cytotoxic T cell functions while suppresses regulatory T cell activities, leading to efficient primary tumor inhibition, pulmonary metastasis prevention, and long-term immunological memory. Thereby, this work provides a generic polymeric approach for precise spatiotemporal regulation of cancer immunometabolism.

  View details for DOI 10.1002/adma.202101410

  View details for PubMedID 34296785

• Semiconducting polymer nano-PROTACs for activatable photo-immunometabolic cancer therapy. Nature communications Zhang, C., Zeng, Z., Cui, D., He, S., Jiang, Y., Li, J., Huang, J., Pu, K. 2021; 12 (1): 2934

  Abstract

  Immunometabolic intervention has been applied to treat cancer via inhibition of certain enzymes associated with intratumoral metabolism. However, small-molecule inhibitors and genetic modification often suffer from insufficiency and off-target side effects. Proteolysis targeting chimeras (PROTACs) provide an alternative way to modulate protein homeostasis for cancer therapy; however, the always-on bioactivity of existing PROTACs potentially leads to uncontrollable protein degradation at non-target sites, limiting their in vivo therapeutic efficacy. We herein report a semiconducting polymer nano-PROTAC (SPNpro) with phototherapeutic and activatable protein degradation abilities for photo-immunometabolic cancer therapy. SPNpro can remotely generate singlet oxygen (1O2) under NIR photoirradiation to eradicate tumor cells and induce immunogenic cell death (ICD) to enhance tumor immunogenicity. Moreover, the PROTAC function of SPNpro is specifically activated by a cancer biomarker (cathepsin B) to trigger targeted proteolysis of immunosuppressive indoleamine 2,3-dioxygenase (IDO) in the tumor of living mice. The persistent IDO degradation blocks tryptophan (Trp)-catabolism program and promotes the activation of effector T cells. Such a SPNpro-mediated in-situ immunometabolic intervention synergizes immunogenic phototherapy to boost the antitumor T-cell immunity, effectively inhibiting tumor growth and metastasis. Thus, this study provides a polymer platform to advance PROTAC in cancer therapy.

  View details for DOI 10.1038/s41467-021-23194-w

  View details for PubMedID 34006860

  View details for PubMedCentralID PMC8131624

• A Polymer Multicellular Nanoengager for Synergistic NIR-II Photothermal Immunotherapy. Advanced materials (Deerfield Beach, Fla.) Xu, C., Jiang, Y., Han, Y., Pu, K., Zhang, R. 2021; 33 (14): e2008061

  Abstract

  Cell-membrane-coated nanoparticles (CCNPs) that integrate the biophysiological advantages of cell membranes with the multifunctionalities of synthetic materials hold great promise in cancer immunotherapy. However, strategies have yet to be revealed to further improve their immunotherapeutic efficacy. Herein, a polymer multicellular nanoengager (SPNE) for synergistic second-near-infrared-window (NIR-II) photothermal immunotherapy is reported. The nanoengager consists of an NIR-II absorbing polymer as the photothermal core, which is camouflaged with fused membranes derived from immunologically engineered tumor cells and dendritic cells (DCs) as the cancer vaccine shell. In association with the high accumulation in lymph nodes and tumors, the multicellular engagement ability of the SPNE enables effective cross-interactions among tumor cells, DCs, and T cells, leading to augmented T cell activation relative to bare or tumor-cell-coated nanoparticles. Upon deep-tissue penetrating NIR-II photoirradiation, SPNE eradicates the tumor and induces immunogenic cell death, further eliciting anti-tumor T cell immunity. Such a synergistic photothermal immunotherapeutic effect eventually inhibits tumor growth, prevents metastasis and procures immunological memory. Thus, this study presents a general cell-membrane-coating approach to develop photo-immunotherapeutic agents for cancer therapy.

  View details for DOI 10.1002/adma.202008061

  View details for PubMedID 33634897

• Molecular Chemiluminescent Probes with a Very Long Near-Infrared Emission Wavelength for in Vivo Imaging. Angewandte Chemie (International ed. in English) Huang, J., Jiang, Y., Li, J., Huang, J., Pu, K. 2021; 60 (8): 3999-4003

  Abstract

  Chemiluminescence imaging is imperative for diagnostics and imaging due to its intrinsically high sensitivity. To improve in vivo detection of biomarkers, chemiluminophores that simultaneously possess near-infrared (NIR) emission and modular structures amenable to construction of activatable probes are highly desired; however, these are rare. Herein, we report two chemiluminophores with record long NIR emission (>750 nm) via integration of dicyanomethylene-4H-benzothiopyran or dicyanomethylene-4H-benzoselenopyran with dioxetane unit. Caging of the chemiluminophores with different cleavable moieties produces NIR chemiluminescence probes (NCPs) that only produce signals upon reaction with reactive oxygen species or enzymes, for example, β-galactosidase, with a tissue-penetration depth of up to 2 cm. Thus, this study provides NIR chemiluminescence molecular scaffolds applicable for in vivo turn-on imaging of versatile biomarkers in deep tissues.

  View details for DOI 10.1002/anie.202013531

  View details for PubMedID 33119955

• Activatable polymer nanoagonist for second near-infrared photothermal immunotherapy of cancer. Nature communications Jiang, Y., Huang, J., Xu, C., Pu, K. 2021; 12 (1): 742

  Abstract

  Nanomedicine in combination with immunotherapy offers opportunities to treat cancer in a safe and effective manner; however, remote control of immune response with spatiotemporal precision remains challenging. We herein report a photothermally activatable polymeric pro-nanoagonist (APNA) that is specifically regulated by deep-tissue-penetrating second near-infrared (NIR-II) light for combinational photothermal immunotherapy. APNA is constructed from covalent conjugation of an immunostimulant onto a NIR-II semiconducting transducer through a labile thermo-responsive linker. Upon NIR-II photoirradiation, APNA mediates photothermal effect, which not only triggers tumor ablation and immunogenic cell death but also initiates the cleavage of thermolabile linker to liberate caged agonist for in-situ immune activation in deep solid tumor (8 mm). Such controlled immune regulation potentiates systemic antitumor immunity, leading to promoted cytotoxic T lymphocytes and helper T cell infiltration in distal tumor, lung and liver to inhibit cancer metastasis. Thereby, the present work illustrates a generic strategy to prepare pro-immunostimulants for spatiotemporal regulation of cancer nano-immunotherapy.

  View details for DOI 10.1038/s41467-021-21047-0

  View details for PubMedID 33531498

  View details for PubMedCentralID PMC7854754

• Second Near-Infrared Photothermal Semiconducting Polymer Nanoadjuvant for Enhanced Cancer Immunotherapy. Advanced materials (Deerfield Beach, Fla.) Li, J., Yu, X., Jiang, Y., He, S., Zhang, Y., Luo, Y., Pu, K. 2021; 33 (4): e2003458

  Abstract

  Immunotherapy has offered new treatment options for cancer; however, the therapeutic benefits are often modest and desired to be improved. A semiconducting polymer nanoadjuvant (SPNII R) with a photothermally triggered cargo release for second near-infrared (NIR-II) photothermal immunotherapy is reported here. SPNII R consists of a semiconducting polymer nanoparticle core as an NIR-II photothermal converter, which is doped with a toll-like receptor (TLR) agonist as an immunotherapy adjuvant and coated with a thermally responsive lipid shell. Upon NIR-II photoirradiation, SPNII R effectively generates heat not only to ablate tumors and induce immunogenic cell death (ICD), but also to melt the lipid layers for on-demand release of the TLR agonist. The combination of ICD and activation of TLR7/TLR8 enhances the maturation of dendritic cells, which amplifies anti-tumor immune responses. Thus, a single treatment of SPNII R-mediated NIR-II photothermal immunotherapy effectively inhibits growth of both primary and distant tumors and eliminates lung metastasis in a murine mouse model. This study thus provides a remote-controlled smart delivery system to synergize photomedicine with immunotherapy for enhanced cancer treatment.

  View details for DOI 10.1002/adma.202003458

  View details for PubMedID 33325584

• Activatable Polymer Nanoenzymes for Photodynamic Immunometabolic Cancer Therapy. Advanced materials (Deerfield Beach, Fla.) Zeng, Z., Zhang, C., Li, J., Cui, D., Jiang, Y., Pu, K. 2021; 33 (4): e2007247

  Abstract

  Tumor immunometabolism contributes substantially to tumor proliferation and immune cell activity, and thus plays a crucial role in the efficacy of cancer immunotherapy. Modulation of immunometabolism to boost cancer immunotherapy is mostly based on small-molecule inhibitors, which often encounter the issues of off-target adverse effects, drug resistance, and unsustainable response. In contrast, enzymatic therapeutics can potentially bypass these limitations but has been less exploited. Herein, an organic polymer nanoenzyme (SPNK) with near-infrared (NIR) photoactivatable immunotherapeutic effects is reported for photodynamic immunometabolic therapy. SPNK is composed of a semiconducting polymer core conjugated with kynureninase (KYNase) via PEGylated singlet oxygen (1 O2 ) cleavable linker. Upon NIR photoirradiation, SPNK generates 1 O2 not only to exert photodynamic effect to induce the immunogenic cell death of cancer, but also to unleash KYNase and trigger its activity to degrade the immunosuppressive kynurenine (Kyn). Such a combinational effect mediated by SPNK promotes the proliferation and infiltration of effector T cells, enhances systemic antitumor T cell immunity, and ultimately permits inhibition of both primary and distant tumors in living mice. Therefore, this study provides a promising photodynamic approach toward remotely controlled enzymatic immunomodulation for improved anticancer therapy.

  View details for DOI 10.1002/adma.202007247

  View details for PubMedID 33306220

• Room-Temperature Phosphorescence Resonance Energy Transfer for Construction of Near-Infrared Afterglow Imaging Agents. Advanced materials (Deerfield Beach, Fla.) Dang, Q., Jiang, Y., Wang, J., Wang, J., Zhang, Q., Zhang, M., Luo, S., Xie, Y., Pu, K., Li, Q., Li, Z. 2020; 32 (52): e2006752

  Abstract

  Afterglow imaging that detects photons after cessation of optical excitation avoids tissue autofluorescence and thus possesses higher sensitivity than traditional fluorescence imaging. Purely organic molecules with room-temperature phosphorescence (RTP) have emerged as a new library of benign afterglow agents. However, most RTP luminogens only emit visible light with shallow tissue penetration, constraining their in vivo applications. This study presents an organic RTP nanoprobe (mTPA-N) with emission in the NIR range for in vivo afterglow imaging. Such a probe is composed of RTP molecule (mTPA) as the phosphorescent generator and an NIR-fluorescent dye as the energy acceptor to enable room-temperature phosphorescence resonance energy transfer (RT-PRET), ultimately resulting in redshifted phosphorescent emission at 780 nm. Because of the elimination of background noise and redshifted afterglow luminescence in a biologically transparent window, mTPA-N permits imaging of lymph nodes in living mice with a high signal-to-noise ratio. This study thus opens up a universal approach to develop organic RTP luminogens into NIR afterglow imaging agents via construction of RT-PRET.

  View details for DOI 10.1002/adma.202006752

  View details for PubMedID 33175432

• Near-Infrared Chemiluminescent Reporters for In Vivo Imaging of Reactive Oxygen and Nitrogen Species in Kidneys ADVANCED FUNCTIONAL MATERIALS Huang, J., Huang, J., Cheng, P., Jiang, Y., Pu, K. 2020; 30 (39)

  View details for DOI 10.1002/adfm.202003628

  View details for Web of Science ID 000558655500001

• Semiconducting Polycomplex Nanoparticles for Photothermal Ferrotherapy of Cancer. Angewandte Chemie (International ed. in English) He, S., Jiang, Y., Li, J., Pu, K. 2020; 59 (26): 10633-10638

  Abstract

  This study reports the development of iron-chelated semiconducting polycomplex nanoparticles (SPFeN) for photoacoustic (PA) imaging-guided photothermal ferrotherapy of cancer. The hybrid polymeric nanoagent comprises a ferroptosis initiator (Fe3+ ) and an amphiphilic semiconducting polycomplex (SPC ) serving as both the photothermal nanotransducer and iron ion chelator. By virtue of poly(ethylene glycol) (PEG) grafting and its small size, SPFeN accumulates in the tumor of living mice after systemic administration, which can be monitored by PA imaging. In the acidic tumor microenvironment, SPFeN generates hydroxyl radicals, leading to ferroptosis; meanwhile, under NIR laser irradiation, it generates localized heat to not only accelerate the Fenton reaction but also implement photothermal therapy. Such a combined photothermal ferrotherapeutic effect of SPFeN leads to minimized dosage of iron compared to previous studies and effectively inhibits the tumor growth in living mice, which is not possible for the controls.

  View details for DOI 10.1002/anie.202003004

  View details for PubMedID 32207214

• Transformable hybrid semiconducting polymer nanozyme for second near-infrared photothermal ferrotherapy. Nature communications Jiang, Y., Zhao, X., Huang, J., Li, J., Upputuri, P. K., Sun, H., Han, X., Pramanik, M., Miao, Y., Duan, H., Pu, K., Zhang, R. 2020; 11 (1): 1857

  Abstract

  Despite its growing promise in cancer treatment, ferrotherapy has low therapeutic efficacy due to compromised Fenton catalytic efficiency in tumor milieu. We herein report a hybrid semiconducting nanozyme (HSN) with high photothermal conversion efficiency for photoacoustic (PA) imaging-guided second near-infrared photothermal ferrotherapy. HSN comprises an amphiphilic semiconducting polymer as photothermal converter, PA emitter and iron-chelating Fenton catalyst. Upon photoirradiation, HSN generates heat not only to induce cytotoxicity but also to enhance Fenton reaction. The increased ·OH generation promotes both ferroptosis and apoptosis, oxidizes HSN (42 nm) and transforms it into tiny segments (1.7 nm) with elevated intratumoral permeability. The non-invasive seamless synergism leads to amplified therapeutic effects including a deep ablation depth (9 mm), reduced expression of metastasis-related proteins and inhibition of metastasis from primary tumor to distant organs. Thereby, our study provides a generalized nanozyme strategy to compensate both ferrotherapy and phototherapeutics for complete tumor regression.

  View details for DOI 10.1038/s41467-020-15730-x

  View details for PubMedID 32312987

  View details for PubMedCentralID PMC7170847

• A Renal-Clearable Macromolecular Reporter for Near-Infrared Fluorescence Imaging of Bladder Cancer. Angewandte Chemie (International ed. in English) Huang, J., Jiang, Y., Li, J., He, S., Huang, J., Pu, K. 2020; 59 (11): 4415-4420

  Abstract

  Bladder cancer (BC) is a prevalent disease with high morbidity and mortality; however, in vivo optical imaging of BC remains challenging because of the lack of cancer-specific optical agents with high renal clearance. Herein, a macromolecular reporter (CyP1) was synthesized for real-time near-infrared fluorescence (NIRF) imaging and urinalysis of BC in living mice. Because of the high renal clearance (ca. 94 % of the injection dosage at 24 h post-injection) and its cancer biomarker (APN=aminopeptidase N) specificity, CyP1 can be efficiently transported to the bladder and specially turn on its NIRF signal to report the detection of BC in living mice. Moreover, CyP1 can be used for optical urinalysis, permitting the ex vivo tracking of tumor progression for therapeutic evaluation and easy translation of CyP2 as an in vitro diagnostic assay. This study not only provides new opportunities for non-invasive diagnosis of BC, but also reveals useful guidelines for the development of molecular reporters for the detection of bladder diseases.

  View details for DOI 10.1002/anie.201911859

  View details for PubMedID 31876017

• A Photolabile Semiconducting Polymer Nanotransducer for Near-Infrared Regulation of CRISPR/Cas9 Gene Editing. Angewandte Chemie (International ed. in English) Lyu, Y., He, S., Li, J., Jiang, Y., Sun, H., Miao, Y., Pu, K. 2019; 58 (50): 18197-18201

  Abstract

  Noninvasive regulation of CRISPR/Cas9 gene editing is conducive to understanding of gene function and development of gene therapy; however, it remains challenging. Herein, a photolabile semiconducting polymer nanotransducer (pSPN) is synthesized to act as the gene vector to deliver CRISPR/Cas9 plasmids into cells and also as the photoregulator to remotely activate gene editing. pSPN comprises a 1 O2 -generating backbone grafted with polyethylenimine brushes through 1 O2 -cleavable linkers. NIR photoirradiation spontaneously triggers the cleavage of gene vectors from pSPN, resulting in the release of CRISPR/Cas9 plasmids and subsequently initiating gene editing. This system affords 15- and 1.8-fold enhancement in repaired gene expression relative to the nonirradiated controls in living cells and mice, respectively. As this approach does not require any specific modifications on biomolecular components, pSPN represents the first generic nanotransducer for in vivo regulation of CRISPR/Cas9 gene editing.

  View details for DOI 10.1002/anie.201909264

  View details for PubMedID 31566854

• A Renal-Clearable Duplex Optical Reporter for Real-Time Imaging of Contrast-Induced Acute Kidney Injury. Angewandte Chemie (International ed. in English) Huang, J., Lyu, Y., Li, J., Cheng, P., Jiang, Y., Pu, K. 2019; 58 (49): 17796-17804

  Abstract

  Despite its high morbidity and mortality, contrast-induced acute kidney injury (CIAKI) remains a diagnostic dilemma because it relies on in vitro detection of insensitive late-stage blood and urinary biomarkers. We report the synthesis of an activatable duplex reporter (ADR) for real-time in vivo imaging of CIAKI. ADR is equipped with chemiluminescence and near-infrared fluorescence (NIRF) signaling channels that can be activated by oxidative stress (superoxide anion, O2.- ) and lysosomal damage (N-acetyl-β-d-glucosaminidase, NAG), respectively. By virtue of its high renal clearance efficiency (80 % injected doses after 24 h injection), ADR detects sequential upregulation of O2.- and NAG in the kidneys of living mice prior to a significant decrease in glomerular filtration rate (GFR) and tissue damage in the course of CIAKI. ADR outperforms the typical clinical assays and detects CIAKI at least 8 h (NIRF) and up to 16 h (chemiluminescence) earlier.

  View details for DOI 10.1002/anie.201910137

  View details for PubMedID 31602731

• Near-Infrared Photoactivatable Semiconducting Polymer Nanoblockaders for Metastasis-Inhibited Combination Cancer Therapy. Advanced materials (Deerfield Beach, Fla.) Li, J., Cui, D., Jiang, Y., Huang, J., Cheng, P., Pu, K. 2019; 31 (46): e1905091

  Abstract

  Inhibition of protein biosynthesis is a promising strategy to develop new therapeutic modalities for cancers; however, noninvasive precise regulation of this cellular event in living systems has been rarely reported. In this study, a semiconducting polymer nanoblockader (SPNB ) is developed that can inhibit intracellular protein synthesis upon near-infrared (NIR) photoactivation to synergize with photodynamic therapy (PDT) for metastasis-inhibited cancer therapy. SPNB is self-assembled from an amphiphilic semiconducting polymer which is grafted with poly(ethylene glycol) conjugated with a protein biosynthesis blockader through a singlet oxygen (1 O2 ) cleavable linker. Such a designed molecular structure not only enables generation of 1 O2 under NIR photoirradiation for PDT, but also permits photoactivation of blockaders to terminate protein translation. Thereby, SPNB exerts a synergistic action to afford an enhanced therapeutic efficacy in tumor ablation. More importantly, SPNB -mediated photoactivation of protein synthesis inhibition precisely and remotely downregulates the expression levels of metastasis-related proteins in tumor tissues, eventually contributing to the complete inhibition of lung metastasis. This study thus proposes a photoactivatable protherapeutic design for metastasis-inhibited cancer therapy.

  View details for DOI 10.1002/adma.201905091

  View details for PubMedID 31566279

• Renal-clearable Molecular Semiconductor for Second Near-Infrared Fluorescence Imaging of Kidney Dysfunction. Angewandte Chemie (International ed. in English) Huang, J., Xie, C., Zhang, X., Jiang, Y., Li, J., Fan, Q., Pu, K. 2019; 58 (42): 15120-15127

  Abstract

  Real-time imaging of kidney function is important to assess the nephrotoxicity of drugs and monitor the progression of renal diseases; however, it remains challenging because of the lack of optical agents with high renal clearance and high signal-to-background ratio (SBR). Herein, a second near-infrared (NIR-II) fluorescent molecular semiconductor (CDIR2) is synthesized for real-time imaging of kidney dysfunction in living mice. CDIR2 not only has a high renal clearance efficiency (≈90 % injection dosage at 24 h post-injection), but also solely undergoes glomerular filtration into urine without being reabsorbed and secreted in renal tubules. Such a unidirectional renal clearance pathway of CDIR2 permits real-time monitoring of kidney dysfunction in living mice upon nephrotoxic exposure. Thus, this study not only introduces a molecular renal probe but also provides useful molecular guidelines to increase the renal clearance efficiency of NIR-II fluorescent agents.

  View details for DOI 10.1002/anie.201909560

  View details for PubMedID 31452298

• An Organic Afterglow Protheranostic Nanoassembly. Advanced materials (Deerfield Beach, Fla.) He, S., Xie, C., Jiang, Y., Pu, K. 2019; 31 (32): e1902672

  Abstract

  Cancer theranostics holds potential promise for precision medicine; however, most existing theranostic nanoagents are simply developed by doping both therapeutic agents and imaging agent into one particle entity, and thus have an "always-on" pharmaceutical effect and imaging signals regardless of their in vivo location. Herein, the development of an organic afterglow protheranostic nanoassembly (APtN) that specifically activates both the pharmaceutical effect and diagnostic signals in response to a tumor-associated chemical mediator (hydrogen peroxide, H2 O2 ) is reported. APtN comprises an amphiphilic macromolecule and a near-infrared (NIR) dye acting as the H2 O2 -responsive afterglow prodrug and the afterglow initiator, respectively. Such a molecular architecture allows APtN to passively target tumors in living mice, specifically release the anticancer drug in the tumor, and spontaneously generate the uncaged afterglow substrate. Upon NIR light preirradiation, the afterglow initiator generates singlet oxygen to react and subsequently transform the uncaged afterglow substrate into an active self-luminescent form. Thus, the intensity of generated afterglow luminescence is correlated with the drug release status, permitting real-time in vivo monitoring of prodrug activation. This study proposes a background-free design strategy toward activatable cancer theranostics.

  View details for DOI 10.1002/adma.201902672

  View details for PubMedID 31206855

• Thermoresponsive Semiconducting Polymer Nanoparticles for Contrast-Enhanced Photoacoustic Imaging ADVANCED FUNCTIONAL MATERIALS Cui, D., Li, P., Zhen, X., Li, J., Jiang, Y., Yu, A., Hu, X., Pu, K. 2019; 29 (38)

  View details for DOI 10.1002/adfm.201903461

  View details for Web of Science ID 000478458400001

• Organic Photodynamic Nanoinhibitor for Synergistic Cancer Therapy. Angewandte Chemie (International ed. in English) Jiang, Y., Li, J., Zeng, Z., Xie, C., Lyu, Y., Pu, K. 2019; 58 (24): 8161-8165

  Abstract

  Despite its great potential in cancer treatment, photodynamic therapy (PDT) often exacerbates hypoxia and subsequently compromises its therapeutic efficacy. To overcome this issue, an organic photodynamic nanoinhibitor (OPNi) has been synthesized that has the additional ability to counteract carbonic anhydrase IX (CA-IX), a molecular target in the hypoxia-mediated signalling cascade. OPNi is composed of a metabolizable semiconducting polymer as the photosensitizer and a CA-IX antagonist conjugated amphiphilic polymer as the matrix. This molecular structure allows OPNi not only to selectively bind CA-IX positive cancer cells to facilitate its tumor accumulation but also to regulate the CA-IX-related pathway. The integration of CA-IX inhibition into the targeted PDT process eventually has a synergistic effect, leading to superior antitumor efficacy over that of PDT alone, as well as the reduced probability of hypoxia-induced cancer metastasis. This study thus proposes a molecular strategy to devise simple yet amplified photosensitizers to conquer the pitfalls of traditional PDT.

  View details for DOI 10.1002/anie.201903968

  View details for PubMedID 30993791

• Redox-Activatable and Acid-Enhanced Nanotheranostics for Second Near-Infrared Photoacoustic Tomography and Combined Photothermal Tumor Therapy. ACS nano Wang, Z., Zhen, X., Upputuri, P. K., Jiang, Y., Lau, J., Pramanik, M., Pu, K., Xing, B. 2019; 13 (5): 5816-5825

  Abstract

  Tumor phototheranostics in the second near-infrared window (NIR-II, 1000-1700 nm) holds great promise due to high spatiotemporal precision, enhanced penetration depth, and therapeutic efficacy. However, current "always-on" NIR-II phototheranostic agents remain restricted by the inherent nonspecificity from the pseudosignal readout and undesirable treatment-related side effects. To address these challenges, herein we explore an activatable and biocompatible nanotheranostics that generates diagnostic and therapeutic effects only after specific activation and enhancement by tumor microenvironmental redox and acid while keeping silent at normal tissues. Such an intelligent "turn-on" chromogenic nanotheranostics allows in vivo nearly zero-background photoacoustic tomography (PAT) and combined effective photothermal tumor therapy (PTT) both in the NIR-II range with minimal adverse effects. In light of the high sensitivity, superior penetration depth, and biocompatibility, this stimuli-activatable NIR-II photo-nanotheranostics provides broad prospects for the investigation and intervention of deep-tissue redox and acid-associated physiological and pathological events.

  View details for DOI 10.1021/acsnano.9b01411

  View details for PubMedID 31034202

• A generic approach towards afterglow luminescent nanoparticles for ultrasensitive in vivo imaging. Nature communications Jiang, Y., Huang, J., Zhen, X., Zeng, Z., Li, J., Xie, C., Miao, Q., Chen, J., Chen, P., Pu, K. 2019; 10 (1): 2064

  Abstract

  Afterglow imaging with long-lasting luminescence after cessation of light excitation provides opportunities for ultrasensitive molecular imaging; however, the lack of biologically compatible afterglow agents has impeded exploitation in clinical settings. This study presents a generic approach to transforming ordinary optical agents (including fluorescent polymers, dyes, and inorganic semiconductors) into afterglow luminescent nanoparticles (ALNPs). This approach integrates a cascade photoreaction into a single-particle entity, enabling ALNPs to chemically store photoenergy and spontaneously decay it in an energy-relay process. Not only can the afterglow profiles of ALNPs be finetuned to afford emission from visible to near-infrared (NIR) region, but also their intensities can be predicted by a mathematical model. The representative NIR ALNPs permit rapid detection of tumors in living mice with a signal-to-background ratio that is more than three orders of magnitude higher than that of NIR fluorescence. The biodegradability of the ALNPs further heightens their potential for ultrasensitive in vivo imaging.

  View details for DOI 10.1038/s41467-019-10119-x

  View details for PubMedID 31048701

  View details for PubMedCentralID PMC6497674

• A Semiconducting Polymer Nano-prodrug for Hypoxia-Activated Photodynamic Cancer Therapy. Angewandte Chemie (International ed. in English) Cui, D., Huang, J., Zhen, X., Li, J., Jiang, Y., Pu, K. 2019; 58 (18): 5920-5924

  Abstract

  Photodynamic therapy (PDT) holds great promise for cancer therapy; however, its efficacy is often compromised by tumor hypoxia. Herein, we report the synthesis of a semiconducting polymer nanoprodrug (SPNpd) that not only efficiently generates singlet oxygen (1 O2 ) under NIR photoirradiation but also specifically activates its chemotherapeutic action in hypoxic tumor microenvironment. SPNpd is self-assembled from a amphiphilic polymer brush, which comprises a light-responsive photodynamic backbone grafted with poly(ethylene glycol) and conjugated with a chemodrug through hypoxia-cleavable linkers. The well-defined and compact nanostructure of SPNpd (30 nm) enables accumulation in the tumor of living mice. Owing to these features, SPNpd exerts synergistic photodynamic and chemo-therapy, and effectively inhibits tumor growth in a xenograft tumor mouse model. This study represents the first hypoxia-activatable phototherapeutic polymeric prodrug system with a high potential for cancer therapy.

  View details for DOI 10.1002/anie.201814730

  View details for PubMedID 30793456

• Photoactivatable Organic Semiconducting Pro-nanoenzymes. Journal of the American Chemical Society Li, J., Huang, J., Lyu, Y., Huang, J., Jiang, Y., Xie, C., Pu, K. 2019; 141 (9): 4073-4079

  Abstract

  Therapeutic enzymes hold great promise for cancer therapy; however, in vivo remote control of enzymatic activity to improve their therapeutic specificity remains challenging. This study reports the development of an organic semiconducting pro-nanoenzyme (OSPE) with a photoactivatable feature for metastasis-inhibited cancer therapy. Upon near-infrared (NIR) light irradiation, this pro-nanoenzyme not only generates cytotoxic singlet oxygen (1O2) for photodynamic therapy (PDT), but also triggers a spontaneous cascade reaction to induce the degradation of ribonucleic acid (RNA) specifically in tumor microenvironment. More importantly, OSPE-mediated RNA degradation is found to downregulate the expression of metastasis-related proteins, contributing to the inhibition of metastasis after treatment. Such a photoactivated and cancer-specific synergistic therapeutic action of OSPE enables complete inhibition of tumor growth and lung metastasis in mouse xenograft model, which is not possible for the counterpart PDT nanoagent. Thus, our study proposes a phototherapeutic-proenzyme approach toward complete-remission cancer therapy.

  View details for DOI 10.1021/jacs.8b13507

  View details for PubMedID 30741538

• Metabolizable Semiconducting Polymer Nanoparticles for Second Near-Infrared Photoacoustic Imaging. Advanced materials (Deerfield Beach, Fla.) Jiang, Y., Upputuri, P. K., Xie, C., Zeng, Z., Sharma, A., Zhen, X., Li, J., Huang, J., Pramanik, M., Pu, K. 2019; 31 (11): e1808166

  Abstract

  Photoacoustic (PA) imaging in the second near-infrared (NIR-II) window (1000-1700 nm) holds great promise for deep-tissue diagnosis due to the reduced light scattering and minimized tissue absorption; however, exploration of such a noninvasive imaging technique is greatly constrained by the lack of biodegradable NIR-II absorbing agents. Herein, the first series of metabolizable NIR-II PA agents are reported based on semiconducting polymer nanoparticles (SPNs). Such completely organic nanoagents consist of π-conjugated yet oxidizable optical polymer as PA generator and hydrolyzable amphiphilic polymer as particle matrix to provide water solubility. The obtained SPNs are readily degraded by myeloperoxidase and lipase abundant in phagocytes, transforming from nonfluorescent nanoparticles (30 nm) into NIR fluorescent ultrasmall metabolites (≈1 nm). As such, these nanoagents can be effectively cleared out via both hepatobiliary and renal excretions after systematic administration, leaving no toxicity to living mice. Particularly these nanoagents possess high photothermal conversion efficiencies and emit bright PA signals at 1064 nm, enabling sensitive NIR-II PA imaging of both subcutaneous tumor and deep brain vasculature through intact skull in living animals at a low systematic dosage. This study thus provides a generalized molecular design toward organic metabolizable semiconducting materials for biophotonic applications in NIR-II window.

  View details for DOI 10.1002/adma.201808166

  View details for PubMedID 30663820

• pH-sensitive and biodegradable charge-transfer nanocomplex for second near-infrared photoacoustic tumor imaging NANO RESEARCH Wang, Z., Upputuri, P., Zhen, X., Zhang, R., Jiang, Y., Ai, X., Zhang, Z., Hu, M., Meng, Z., Lu, Y., Zheng, Y., Pu, K., Pramanik, M., Xing, B. 2019; 12 (1): 49-55

  View details for DOI 10.1007/s12274-018-2175-9

  View details for Web of Science ID 000453629900006

• Cell Membrane Coated Semiconducting Polymer Nanoparticles for Enhanced Multimodal Cancer Phototheranostics. ACS nano Li, J., Zhen, X., Lyu, Y., Jiang, Y., Huang, J., Pu, K. 2018; 12 (8): 8520-8530

  Abstract

  Phototheranostic nanoagents are promising for early diagnosis and precision therapy of cancer. However, their imaging ability and therapeutic efficacy are often limited due to the presence of delivery barriers in the tumor microenvironment. Herein, we report the development of organic multimodal phototheranostic nanoagents that can biomimetically target cancer-associated fibroblasts in the tumor microenvironment for enhanced multimodal imaging-guided cancer therapy. Such biomimetic nanocamouflages comprise a near-infrared (NIR) absorbing semiconducting polymer nanoparticle (SPN) coated with the cell membranes of activated fibroblasts. The homologous targeting mechanism allows the activated fibroblast cell membrane coated SPN (AF-SPN) to specifically target cancer-associated fibroblasts, leading to enhanced tumor accumulation relative to the uncoated and cancer cell membrane coated counterparts after systemic administration in living mice. As such, AF-SPN not only provides stronger NIR fluorescence and photoacoustic signals to detect tumors but also generates enhanced cytotoxic heat and singlet oxygen to exert combinational photothermal and photodynamic therapy, ultimately leading to an antitumor efficacy higher than that of the counterparts. This study introduces an organic phototheranostic system that biomimetically targets the component in the tumor microenvironment for enhanced multimodal cancer theranostics.

  View details for DOI 10.1021/acsnano.8b04066

  View details for PubMedID 30071159

• Multimodal Biophotonics of Semiconducting Polymer Nanoparticles. Accounts of chemical research Jiang, Y., Pu, K. 2018; 51 (8): 1840-1849

  Abstract

  Biophotonics as an interdisciplinary frontier plays an increasingly important role in modern biomedical science. Optical agents are generally involved in biophotonics to interpret biomolecular events into readable optical signals for imaging and diagnosis or to convert photons into other forms of energy (such as heat, mechanical force, or chemical radicals) for therapeutic intervention and biological stimulation. Development of new optical agents including metallic nanoparticles, quantum dots, up-conversion nanoparticles, carbon dots, and silica nanoparticles has contributed to the advancement of this field. However, most of these agents have their own merits and demerits, making them less effective as multimodal biophotonic platforms. In this Account, we summarize our recent work on the development of near-infrared (NIR) semiconducting polymer nanoparticles (SPNs) as multimodal light converters for advanced biophotonics. SPNs are composed of π-electron delocalized semiconducting polymers (SPs) and often possess the advantages of good biocompatibility, high photostability, and large absorption coefficients. Because the photophysical properties of SPNs are mainly determined by the molecular structures of the precursor polymers, molecular engineering allows us to fine tune their photophysical processes to obtain different optical responses, even to light in the second NIR window (1000-1700 nm). Meanwhile, the facile nanoformulation methods of SPNs enable alteration of their outer and inner structures for diverse biological interactions. The unique photophysical properties of SPNs have brought about ultrasensitive deep-tissue molecular imaging. NIR-absorbing SPNs with strong charge-transfer backbones can convert photoenergy into mechanical acoustic waves, permitting photoacoustic imaging that bypasses the issue of light scattering and reaches the centimeter tissue penetration depth. Differently, phenylenevinylene-containing SPNs can store photon energy via chemical defects and emit long-NIR afterglow luminescence with a half-life of ∼6 min after cessation of light excitation. Such an afterglow process avoids tissue autofluorescence, giving rise to ultrahigh signal-to-background ratios. So far, SPN-based molecular photoacoustic or afterglow probes have been developed to image disease tissues (tumors), biomarkers (biothiols and reactive oxygen species), and physiological indexes (pH and temperature) in different preclinical animal models. The synthetic flexibility of SPNs further permits light-modulated biological and therapeutic interventions. Till now, SPNs with high photothermal conversion efficiencies have been shaped into photothermal transducers to remotely regulate biological events including protein ion channels, enzymatic activity, and gene expression. In conjunction with the desired biodistribution and tumor-homing ability, SPNs have been doped or coated with other inorganic agents for amplified photothermal or self-regulated photodynamic cancer therapy. This Account thus demonstrates that SPNs serve as a multimodal biophotonic nanoplatform to provide unprecedented opportunities for molecular imaging, noninvasive bioactivation, and advanced therapy.

  View details for DOI 10.1021/acs.accounts.8b00242

  View details for PubMedID 30074381

• Molecular Fluorescence and Photoacoustic Imaging in the Second Near-Infrared Optical Window Using Organic Contrast Agents. Advanced biosystems Jiang, Y., Pu, K. 2018; 2 (5): e1700262

  Abstract

  Noninvasive near-infrared (NIR) light ranging from 650 to 1000 nm (NIR-I) is widely employed in fundamental research and clinical applications; however, a recently discovered second NIR (NIR-II) window from 1000 to 1700 nm exhibits even better deep-tissue imaging capability due to reduced photon scattering, minimized tissue autofluorescence, and increased applicable power at longer wavelengths. This review focuses on recent advances of organic contrast agents developed for in vivo fluorescence and photoacoustic imaging in the NIR-II optical window. The superiority of the NIR-II over the NIR-I window for molecular imaging is first discussed in detail, followed by discussion of fluorescence and photoacoustic imaging of cancer, vasculature, and the brain using organic contrast agents in the NIR-II window. At last, challenges and perspectives of organic contrast agents for NIR-II in vivo imaging are suggested.

  View details for DOI 10.1002/adbi.201700262

  View details for PubMedID 33103854

• Semiconducting Polymer Nanoenzymes with Photothermic Activity for Enhanced Cancer Therapy. Angewandte Chemie (International ed. in English) Li, J., Xie, C., Huang, J., Jiang, Y., Miao, Q., Pu, K. 2018; 57 (15): 3995-3998

  Abstract

  Regulation of enzyme activity is fundamentally challenging but practically meaningful for biology and medicine. However, noninvasive remote control of enzyme activity in living systems has been rarely demonstrated and exploited for therapy. Herein, we synthesize a semiconducting polymer nanoenzyme with photothermic activity for enhanced cancer therapy. Upon near-infrared (NIR) light irradiation, the activity of the nanoenzyme can be enhanced by 3.5-fold to efficiently digest collagen in the tumor extracellular matrix (ECM), leading to enhanced nanoparticle accumulation in tumors and consequently improved photothermal therapy (PTT). This study thus provides a promising strategy to remotely regulate enzyme activity for cancer therapy.

  View details for DOI 10.1002/anie.201800511

  View details for PubMedID 29417709

• Dual-Peak Absorbing Semiconducting Copolymer Nanoparticles for First and Second Near-Infrared Window Photothermal Therapy: A Comparative Study. Advanced materials (Deerfield Beach, Fla.) Jiang, Y., Li, J., Zhen, X., Xie, C., Pu, K. 2018; 30 (14): e1705980

  Abstract

  Near-infrared (NIR) light is widely used for noninvasive optical diagnosis and phototherapy. However, current research focuses on the first NIR window (NIR-I, 650-950 nm), while the second NIR window (NIR-II, 1000-1700 nm) is far less exploited. The development of the first organic photothermal nanoagent (SPNI-II ) with dual-peak absorption in both NIR windows and its utilization in photothermal therapy (PTT) are reported herein. Such a nanoagent comprises a semiconducting copolymer with two distinct segments that respectively and identically absorb NIR light at 808 and 1064 nm. With the photothermal conversion efficiency of 43.4% at 1064 nm generally higher than other inorganic nanomaterials, SPNI-II enables superior deep-tissue heating at 1064 nm over that at 808 nm at their respective safety limits. Model deep-tissue cancer PTT at a tissue depth of 5 mm validates the enhanced antitumor effect of SPNI-II when shifting laser irradiation from the NIR-I to the NIR-II window. The good biodistribution and facile synthesis of SPNI-II also allow it to be doped with an NIR dye for fluorescence-imaging-guided NIR-II PTT through systemic administration. Thus, this study paves the way for the development of new polymeric nanomaterials to advance phototherapy.

  View details for DOI 10.1002/adma.201705980

  View details for PubMedID 29457284

• Compact Plasmonic Blackbody for Cancer Theranosis in the Near-Infrared II Window. ACS nano Zhou, J., Jiang, Y., Hou, S., Upputuri, P. K., Wu, D., Li, J., Wang, P., Zhen, X., Pramanik, M., Pu, K., Duan, H. 2018; 12 (3): 2643-2651

  Abstract

  We have developed a class of blackbody materials, i. e., hyperbranched Au plasmonic blackbodies (AuPBs), of compact sizes (<50 nm). The AuPBs were prepared in a seedless and surfactant-free approach based on the use of mussel-inspired dopamine. Strong intraparticle plasmonic coupling among branches in close proximity leads to intense and uniform broadband absorption across 400-1350 nm. The blackbody absorption imparts the compact AuPB with a superior photothermal efficiency of >80% and closely matched photothermal activity in the first near-infrared (NIR-I) and the second near-infrared (NIR-II) spectral windows, making it a rare broadband theranostic probe for integrated photoacoustic imaging and photothermal therapy (PTT). Our comparative study, using the same probe, has demonstrated that the improved PTT outcome of NIR-II over NIR-I primarily results from its higher maximum permission exposure (MPE) rather than the deeper tissue penetration favored by longer wavelengths. The compact plasmonic broadband nanoabsorbers with tailored surface properties hold potential for a wide spectrum of light-mediated applications.

  View details for DOI 10.1021/acsnano.7b08725

  View details for PubMedID 29438610

• Enhancing Both Biodegradability and Efficacy of Semiconducting Polymer Nanoparticles for Photoacoustic Imaging and Photothermal Therapy. ACS nano Lyu, Y., Zeng, J., Jiang, Y., Zhen, X., Wang, T., Qiu, S., Lou, X., Gao, M., Pu, K. 2018; 12 (2): 1801-1810

  Abstract

  Theranostic nanoagents are promising for precision medicine. However, biodegradable nanoagents with the ability for photoacoustic (PA) imaging guided photothermal therapy (PTT) are rare. We herein report the development of biodegradable semiconducting polymer nanoparticles (SPNs) with enhanced PA and PTT efficacy for cancer therapy. The design capitalizes on the enzymatically oxidizable nature of vinylene bonds in conjunction with polymer chemistry to synthesize a biodegradable semiconducting polymer (DPPV) and transform it into water-soluble nanoparticles (SPNV). As compared with its counterpart SPN (SPNT), the presence of vinylene bonds within the polymer backbone also endows SPNV with a significantly enhanced mass absorption coefficient (1.3-fold) and photothermal conversion efficacy (2.4-fold). As such, SPNV provides the PA signals and the photothermal maximum temperature higher than SPNT, allowing detection and photothermal ablation of tumors in living mice in a more sensitive and effective way. Our study thus reveals a general molecular design to enhance the biodegradability of optically active polymer nanoparticles while dramatically elevating their imaging and therapeutic capabilities.

  View details for DOI 10.1021/acsnano.7b08616

  View details for PubMedID 29385336

• Semiconducting Photothermal Nanoagonist for Remote-Controlled Specific Cancer Therapy. Nano letters Zhen, X., Xie, C., Jiang, Y., Ai, X., Xing, B., Pu, K. 2018; 18 (2): 1498-1505

  Abstract

  Nanomedicine have shown success in cancer therapy, but the pharmacological actions of most nanomedicine are often nonspecific to cancer cells because of utilization of the therapeutic agents that induce cell apoptosis from inner organelles. We herein report the development of semiconducting photothermal nanoagonists that can remotely and specifically initiate the apoptosis of cancer cells from cell membrane. The organic nanoagonists comprise semiconducting polymer nanoparticles (SPNs) and capsaicin (Cap) as the photothermally responsive nanocarrier and the agonist for activation of transient receptor potential cation channel subfamily V member 1 (TRPV1), respectively. Under multiple NIR laser irradiation at the time scale of seconds, the nanoagonists can repeatedly and locally release Cap to multiply activate TRPV1 channels on the cellular membrane; the cumulative effect is the overinflux of ions in mitochondria followed by the induction of cell apoptosis specifically for TRPV1-postive cancer cells. Multiple transient activation of TRPV1 channels is essential to induce such a cell death both in vitro and in vivo because both free Cap and simple Cap-encapsulated nanoparticles fail to do so. The photothermally triggered release also ensures a high local concentration of the TRPV1 agonist at tumor site, permitting specific cancer cell therapy at a low systemic administration dosage. Our study thus demonstrates the first example of ion-channel-specific and remote-controlled drug-delivery system for cancer cell therapy.

  View details for DOI 10.1021/acs.nanolett.7b05292

  View details for PubMedID 29342359

• Photoacoustic imaging at 1064 nm wavelength with exogenous contrast agents Upputuri, P., Jiang, Y., Pu, K., Pramanik, M., Oraevsky, A. A., Wang, L. V. SPIE-INT SOC OPTICAL ENGINEERING. 2018

  View details for DOI 10.1117/12.2287084

  View details for Web of Science ID 000453069300042

• Amphiphilic semiconducting polymer as multifunctional nanocarrier for fluorescence/photoacoustic imaging guided chemo-photothermal therapy. Biomaterials Jiang, Y., Cui, D., Fang, Y., Zhen, X., Upputuri, P. K., Pramanik, M., Ding, D., Pu, K. 2017; 145: 168-177

  Abstract

  Chemo-photothermal nanotheranostics has the advantage of synergistic therapeutic effect, providing opportunities for optimized cancer therapy. However, current chemo-photothermal nanotheranostic systems generally comprise more than three components, encountering the potential issues of unstable nanostructures and unexpected conflicts in optical and biophysical properties among different components. We herein synthesize an amphiphilic semiconducting polymer (PEG-PCB) and utilize it as a multifunctional nanocarrier to simplify chemo-photothermal nanotheranostics. PEG-PCB has a semiconducting backbone that not only serves as the diagnostic component for near-infrared (NIR) fluorescence and photoacoustic (PA) imaging, but also acts as the therapeutic agent for photothermal therapy. In addition, the hydrophobic backbone of PEG-PCB provides strong hydrophobic and π-π interactions with the aromatic anticancer drug such as doxorubicin for drug encapsulation and delivery. Such a trifunctionality of PEG-PCB eventually results in a greatly simplified nanotheranostic system with only two components but multimodal imaging and therapeutic capacities, permitting effective NIR fluorescence/PA imaging guided chemo-photothermal therapy of cancer in living mice. Our study thus provides a molecular engineering approach to integrate essential properties into one polymer for multimodal nanotheranostics.

  View details for DOI 10.1016/j.biomaterials.2017.08.037

  View details for PubMedID 28866477

• Broadband Absorbing Semiconducting Polymer Nanoparticles for Photoacoustic Imaging in Second Near-Infrared Window. Nano letters Jiang, Y., Upputuri, P. K., Xie, C., Lyu, Y., Zhang, L., Xiong, Q., Pramanik, M., Pu, K. 2017; 17 (8): 4964-4969

  Abstract

  Photoacoustic (PA) imaging holds great promise for preclinical research and clinical practice. However, most studies rely on the laser wavelength in the first near-infrared (NIR) window (NIR-I, 650-950 nm), while few studies have been exploited in the second NIR window (NIR-II, 1000-1700 nm), mainly due to the lack of NIR-II absorbing contrast agents. We herein report the synthesis of a broadband absorbing PA contrast agent based on semiconducting polymer nanoparticles (SPN-II) and apply it for PA imaging in NIR-II window. SPN-II can absorb in both NIR-I and NIR-II regions, providing the feasibility to directly compare PA imaging at 750 nm with that at 1064 nm. Because of the weaker background PA signals from biological tissues in NIR-II window, the signal-to-noise ratio (SNR) of SPN-II resulted PA images at 1064 nm can be 1.4-times higher than that at 750 nm when comparing at the imaging depth of 3 cm. The proof-of-concept application of NIR-II PA imaging is demonstrated in in vivo imaging of brain vasculature in living rats, which showed 1.5-times higher SNR as compared with NIR-I PA imaging. Our study not only introduces the first broadband absorbing organic contrast agent that is applicable for PA imaging in both NIR-I and NIR-II windows but also reveals the advantages of NIR-II over NIR-I in PA imaging.

  View details for DOI 10.1021/acs.nanolett.7b02106

  View details for PubMedID 28654292

• Advanced Photoacoustic Imaging Applications of Near-Infrared Absorbing Organic Nanoparticles. Small (Weinheim an der Bergstrasse, Germany) Jiang, Y., Pu, K. 2017; 13 (30)

  Abstract

  Progress of nanotechnology in recent years has stimulated fast development of nanoparticles in biomedical research. Photoacoustic (PA) imaging as an emerging non-invasive technique in molecular imaging has improved imaging depth relative to conventional optical imaging, demonstrating great potential in clinical applications. The convergence of nanotechnology and PA imaging has enabled a broad spectrum of new opportunities in fundamental biology and translation medicine. This review focuses on the recent advances of organic nanoparticles in PA imaging applications. Near-infrared absorbing organic nanoparticles are classified and discussed according to their different imaging applications, which include tumor imaging, gastrointestinal imaging, sentinel lymph node imaging, disease microenvironment imaging and real-time drug imaging. The chemistry and PA properties of organic nanoparticles are discussed in details to highlight their own merits, and their challenges and perspectives in PA imaging are also discussed.

  View details for DOI 10.1002/smll.201700710

  View details for PubMedID 28597608