Molecularly generated light and its biomedical applications.

Molecularly generated light, referred to here as "molecular light", mainly includes bioluminescence, chemiluminescence, and Cerenkov luminescence. Molecular light possesses unique dual features of being both a molecule and a source of light. Its molecular nature enables it to be delivered as molecules to regions deep within the body, overcoming the limitations of natural sunlight and physically generated light sources like lasers and LEDs. Simultaneously, its light properties make it valuable for applications such as imaging, photodynamic therapy, photo-oxidative therapy, and photobiomodulation. In this review article, we provide an updated overview of the diverse applications of molecular light and discuss the strengths and weaknesses of molecular light across various domains. Lastly, we present forward-looking perspectives on the potential of molecular light in the realms of molecular imaging, photobiological mechanisms, therapeutic applications, and photobiomodulation. While some of these perspectives may be considered bold and contentious, our intent is to inspire further innovations in the field of molecular light applications.

Molecular radio afterglow probes for cancer radiodynamic theranostics.

X-ray-induced afterglow and radiodynamic therapy tackle the tissue penetration issue of optical imaging and phototherapy. However, inorganic nanophosphors used in this therapy have their radio afterglow dynamic function as always on, limiting the detection specificity and treatment efficacy. Here we report organic luminophores (IDPAs) with near-infrared afterglow and 1O2 production after X-ray irradiation for cancer theranostics. The in vivo radio afterglow of IDPAs is >25.0 times brighter than reported inorganic nanophosphors, whereas the radiodynamic production of 1O2 is >5.7 times higher than commercially available radio sensitizers. The modular structure of IDPAs permits the development of a smart molecular probe that only triggers its radio afterglow dynamic function in the presence of a cancer biomarker. Thus, the probe enables the ultrasensitive detection of a diminutive tumour (0.64 mm) with superb contrast (tumour-to-background ratio of 234) and tumour-specific radiotherapy for brain tumour with molecular precision at low dosage. Our work reveals the molecular guidelines towards organic radio afterglow agents and highlights new opportunities for cancer radio theranostics.

A Semiconducting Iron-Chelating Nano-immunomodulator for Specific and Sensitized Sono-metallo-immunotherapy of Cancer.

Sono-immunotherapy holds great potential for deep tumor inhibition; however, smart sono-therapeutic agents to simultaneously eliminate 'domestic' tumor cells and regulate the 'community' tumor immune microenvironment have rarely been developed. Herein, we report a spatiotemporally controllable semiconducting iron-chelated nano-metallomodulator (SINM) for hypersensitive sono-metallo-immunotherapy of cancer. SINM consists of a semiconducting polymer (SP) backbone chelating iron ions (Fe3+ ) with thiophene-based Schiff base structure, and a hydrophilic side chain. Upon accumulation in tumors after systemic administration, SINM specifically arouses ferroptosis and M1 macrophage polarization due to its response toward the tumor redox environment; meanwhile, the chelation of Fe3+ enhances the sono-sensitizing effect of SPs, leading to enhanced generation of reactive oxygen species for immunogenic cell death. Such combined sonodynamic metallo-immunotherapy of SINM efficiently ablates deep tumor and spatiotemporally regulates immunophenotypes.

Activatable Immunoprotease Nanorestimulator for Second Near-Infrared Photothermal Immunotherapy of Cancer.

Photothermal immunotherapy is a combinational cancer therapy modality, wherein the photothermal process can noninvasively ablate cancer and efficiently trigger cancer immunogenic cell death to ignite antitumor immunity. However, cancer cells can resist the cytotoxic lymphocyte-mediated antitumor effect via expressing serine protease inhibitory proteins (serpins) to deactivate proteolytic immunoproteases. Herein, we report a smart polymer nanoagonist (SPND) with second near-infrared (NIR-II) phototherapeutic ablation and tumor-specific immunoprotease granzyme B (GrB) restimulation for cancer photothermal immunotherapy. SPND has a semiconducting polymer backbone grafted with a small-molecule inhibitor of serpinB9 (Sb9i) via a glutathione (GSH)-cleavable linker. Once in the tumor, Sb9i can be specifically liberated from SPND to inhibit serpinB9, restimulating the activity of GrB to enhance cancer immunotherapy. Moreover, SPND induces photothermal therapy for direct tumor ablation and immunogenic cancer cell death (ICD) under NIR-II photoirradiation. Therefore, such a smart nanoagonist represents a way toward combination photothermal immunotherapy (PTI).

Near-Infrared Photodynamic Chemiluminescent Probes for Cancer Therapy and Metastasis Detection.

There is growing interest in the development of chemiluminescence (CL) probes for phototheranostics because of their minimized tissue autofluorescence. However, due to a lack of near-infrared (NIR)-absorbing chemiluminophores, current probes for NIR CL-guided phototherapy are based on nanoparticles made up of multiple components. We report bright unimolecular chemiluminophores with NIR absorptions and emissions, long CL half-lives and ideal photodynamic efficiency. One luminophore is modified into an activatable probe, DBPOL , with a turn-on CL signal and photodynamic activity that are specific to a cancer biomarker. The highly sensitive DBPOL allows CL-guided photodynamic therapy which completely inhibits tumor growth and lung metastasis in mouse models, and can be applied for noninvasive monitoring of lung metastasis. We provide molecular guidelines for NIR-absorbing CL probes for imaging-guided phototherapy.

A Polymeric Extracellular Matrix Nanoremodeler for Activatable Cancer Photo-Immunotherapy.

Cancer immunotherapy has shown tremendous potential to train the intrinsic immune system against malignancy in the clinic. However, the extracellular matrix (ECM) in tumor microenvironment is a formidable barrier that not only restricts the penetration of therapeutic drugs but also prevents the infiltration of antitumor immune cells. We herein report a semiconducting polymer-based ECM nanoremodeler (SPNcb) to combine photodynamic antitumor activity with cancer-specific inhibition of collagen-crosslinking enzymes (lysyl oxidase (LOX) family) for activatable cancer photo-immunotherapy. SPNcb is self-assembled from an amphiphilic semiconducting polymer conjugated with a LOX inhibitor (ß-aminopropionitrile, BAPN) via a cancer biomarker (cathepsin B, CatB)-cleavable segment. BAPN can be exclusively activated to inhibit LOX activity in the presence of the tumor-overexpressed CatB, thus blocking collagen crosslinking and decreasing ECM stiffness. Such an ECM nanoremodeler synergizes immunogenic phototherapy and checkpoint blockade immunotherapy to improve the tumor infiltration of cytotoxic T cells, inhibiting tumor growth and metastasis.

Checkpoint Nano-PROTACs for Activatable Cancer Photo-Immunotherapy.

Checkpoint immunotherapy holds great potential to treat malignancies via blocking the immunosuppressive signaling pathways, which however suffers from inefficiency and off-target adverse effects. Herein, checkpoint nano-proteolysis targeting chimeras (nano-PROTACs) in combination with photodynamic tumor regression and immunosuppressive protein degradation to block checkpoint signaling pathways for activatable cancer photo-immunotherapy are reported. These nano-PROTACs are composed of a photosensitizer (protoporphyrin IX, PpIX) and an Src homology 2 domain-containing phosphatase 2 (SHP2)-targeting PROTAC peptide (aPRO) via a caspase 3-cleavable segment. aPRO is activated by the increased expression of caspase 3 in tumor cells after phototherapeutic treatment and induces targeted degradation of SHP2 via the ubiquitin-proteasome system. The persistent depletion of SHP2 blocks the immunosuppressive checkpoint signaling pathways (CD47/SIRPα and PD-1/PD-L1), thus reinvigorating antitumor macrophages and T cells. Such a checkpoint PROTAC strategy synergizes immunogenic phototherapy to boost antitumor immune response. Thus, this study represents a generalized PROTAC platform to modulate immune-related signaling pathways for improved anticancer therapy.

Activating Nanomedicines with Electromagnetic Energy for Deep-Tissue Induction of Immunogenic Cell Death in Cancer Immunotherapy.

Immunotherapy is an attractive approach for cancer therapy, while its antitumor efficacy is still limited, especially for non-immunogenic tumors. Nanomedicines can be utilized to convert the non-immunogenic "cold" tumors to immunogenic "hot" tumors via inducing immunogenic cell death (ICD), thereby promoting the antitumor immune response. Some nanomedicines that can produce local heat and reactive oxygen species upon the stimulation of electromagnetic energy are the main candidates for inducing the ICD effect. However, their applications are often restricted due to the poor tissue penetration depths of electromagnetic energy, such as light. By contrast, ultrasound, X-ray, alternating magnetic field, and microwave show excellent tissue penetration depths and thereby can be used for sonodynamic therapy, radiotherapy, magnetic hyperthermia therapy, and microwave ablation therapy, all of which can effectively induce ICD. Herein, the combination of deep-tissue electromagnetic energy with nanomedicines for inducing ICD and cancer immunotherapy are summarized. In particular, the designs of nanomedicines to amplify ICD effect in the presence of deep-tissue electromagnetic energy and sensitize tumors to various immunotherapies will be discussed. At the end of this review, a brief conclusion and discussion of current challenges and further perspectives in this subfield are provided.

Recent advances in dual- and multi-responsive nanomedicines for precision cancer therapy.

Nanomedicines have been regarded as a potential approach in the field of cancer treatment due to their unique advantages. Although improved therapeutic efficacy can be achieved, the applications of most traditional nanomedicines are still limited by severe side effects resulting from unintended retention of therapeutic agents in non-diseased tissues. To increase the controllability of therapeutic agent accumulation in targeting sites (such as tumors), stimuli-responsive nanomedicines that realize drug release in response to exogenous or endogenous stimuli have been developed. In these stimuli-responsive nanomedicines, most of them are activated by mono type of stimulus, and therefore show unsatisfactory selectivity and specificity. In contrast, dual- and multi-responsive nanomedicines that integrate different responsive components into a signal nanoplatform can allow drug release in a more safe and effective manner, leading to both improved therapeutic efficacy and reduced systemic toxicity. Herein, we summarize recent advances in precision cancer therapy by using dual- and multi-responsive nanomedicines. The design strategies and working mechanisms of these dual- and multi-responsive nanomedicines and their applications in chemotherapy, phototherapy, and immunotherapy of cancer are introduced in detail. The existing challenges and future prospects are finally discussed in anticipation of accelerating the clinical translation of these nanomedicines.

Semiconducting Polymer Nanoparticles for Photoactivatable Cancer Immunotherapy and Imaging of Immunoactivation.

Immunotherapy that stimulates the body's own immune system to kill cancer cells has emerged as a promising cancer therapeutic method. However, some types of cancer exhibited a low response rate to immunotherapy, and the high risk of immune-related side effects has been aroused during immunotherapy, which greatly restrict its broad applications in cancer therapy. Phototherapy that uses external light to trigger the therapeutic process holds advantages including high selectivity and efficiency, and low side effects. Recently, it has been proven to be able to stimulate immune response in the tumor region by inducing immunogenic cell death (ICD), the process of which was termed photo-immunotherapy, dramatically improving therapeutic specificity over conventional immunotherapy in several aspects. Among numerous optical materials for photo-immunotherapy, semiconducting polymer nanoparticles (SPNs) have gained more and more attention owing to their excellent optical properties and good biocompatibility. In this review, we summarize recent developments of SPNs for immunotherapy and imaging of immunoactivation. Different therapeutic modalities triggered by SPNs including photo-immunotherapy and photo-immunometabolic therapy are first introduced. Then, applications of SPNs for real-time monitoring immunoactivation are discussed. Finally, the conclusion and future perspectives of this research field are given.

Bioenzyme-based nanomedicines for enhanced cancer therapy.

Bioenzymes that catalyze reactions within living systems show a great promise for cancer therapy, particularly when they are integrated with nanoparticles to improve their accumulation into tumor sites. Nanomedicines can deliver toxic bioenzymes into cancer cells to directly cause their death for cancer treatment. By modulating the tumor microenvironment, such as pH, glucose concentration, hypoxia, redox levels and heat shock protein expression, bioenzyme-based nanomedicines play crucial roles in improving the therapeutic efficacy of treatments. Moreover, bioenzyme-mediated degradation of the major components in tumor extracellular matrix greatly increases the penetration and retention of nanoparticles in deep tumors and infiltration of immune cells into tumor tissues, thus enhancing the efficacies of chemotherapy, phototherapy and immunotherapy. In this review, we summarize the recent progresses of bioenzyme-based nanomedicines for enhanced cancer therapy. The design and working mechanisms of the bioenzyme-based nanomedicines to achieve enhanced chemotherapy, photothermal therapy, photodynamic therapy, chemodynamic therapy, radiotherapy and immunotherapy are introduced in detail. At the end of this review, a conclusion and current challenges and perspectives in this field are given.

Tumor-Microenvironment-Activatable Polymer Nano-Immunomodulator for Precision Cancer Photoimmunotherapy.

Cancer nanomedicine combined with immunotherapy has become a promising strategy for treating cancer in terms of safety and potency; however, precise regulation of the activation of antitumor immunity remains challenging. Herein, a smart semiconducting polymer nano-immunomodulator (SPNI), which responds to the acidic tumor microenvironment (TME), for precision photodynamic immunotherapy of cancer, is reported. The SPNI is self-assembled by a near-infrared (NIR)-absorbing semiconducting polymer and an amphipathic polymer conjugated with a Toll-like receptor 7 (TLR7) agonist via an acid-labile linker. Upon arrival at tumor site, SPNI undergoes hydrolysis and triggers an efficient liberation of TLR7 agonist in response to the acidic TME for dendritic cell activation. Moreover, SPNI exerts photodynamic effects for direct tumor eradication and immunogenic cancer cell death under NIR photoirradiation. The synergistic action of released immunogenic factors and acidic-TME-activated TLR7 agonist can serve as an in situ generated cancer vaccine to evoke strong antitumor activities. Notably, such localized immune activation boosts systemic antitumor immune responses, resulting in enhanced cytotoxic CD8+ T infiltration to inhibit tumor growth and metastasis. Thereby, this work presents a general strategy to devise prodrug of immunotherapeutics for precise regulation of cancer immunotherapy.

Smart Nano-PROTACs Reprogram Tumor Microenvironment for Activatable Photo-metabolic Cancer Immunotherapy.

Protease inhibitors can modulate intratumoral metabolic processes to reprogram the immunosuppressive tumor microenvironment (TME), which however suffer from the limited efficacy and off-targeted side effects. We report smart nano-proteolysis targeting chimeras (nano-PROTACs) with phototherapeutic ablation and cancer-specific protein degradation to reprogram the TME for photo-metabolic cancer immunotherapy. This nano-PROTAC has a semiconducting polymer backbone linked with a cyclooxygenase 1/2 (COX-1/2)-targeting PROTAC peptide (CPP) via a cathepsin B (CatB)-cleavable segment. CPP can be activated by the tumor-overexpressed CatB to induce the degradation of COX-1/2 via the ubiquitin-proteasome system. The persistent degradation of COX-1/2 depletes their metabolite prostaglandin E2 which is responsible for activation of immune suppressor cells. Such a smart PROTAC strategy synergized with phototherapy specifically reprograms the immunosuppressive TME and reinvigorates antitumor immunity.

Second Near-Infrared Light-Activatable Polymeric Nanoantagonist for Photothermal Immunometabolic Cancer Therapy.

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.

Semiconducting polymer nano-PROTACs for activatable photo-immunometabolic cancer therapy.

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.

Photoacoustic Imaging and Photothermal Therapy of Semiconducting Polymer Nanoparticles: Signal Amplification and Second Near-Infrared Construction.

Photoacoustic (PA) imaging and photothermal therapy (PTT) have attracted extensive attention in disease diagnosis and treatment. Although many exogenous contrast agents have been developed for PA imaging and PTT, the design guidelines to amplify their imaging and therapy performances remain challenging and are highly demanded. Semiconducting polymer nanoparticles (SPNs) composed of polymers with π-electron delocalized backbones can be designed to amplify their PA imaging and PTT performance, because of their clear structure-property relation and versatility in modifying their molecular structures to tune their photophysical properties. This review summarizes the recent advances in the photoacoustic imaging and photothermal therapy applications of semiconducting polymer nanoparticles with a focus on signal amplification and second near-infrared (NIR-II, 1000-1700 nm) construction. The strategies such as structure-property screening, fluorescence quenching, accelerated heat dissipation, and size-dependent heat dissipation are first discussed to amplify the PA brightness of SPNs for in vivo PA. The molecular approaches to shifting the absorption of SPNs for NIR-II PA imaging and PTT are then introduced so as to improve the tissue penetration depth for diagnosis and therapy. At last, current challenges and perspectives of SPNs in the field of imaging and therapy are discussed.

Second Near-Infrared Photothermal Semiconducting Polymer Nanoadjuvant for Enhanced Cancer Immunotherapy.

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.

Photoactivatable Protherapeutic Nanomedicine for Cancer.

Therapeutic systems with site-specific pharmaceutical activation hold great promise to enhance therapeutic efficacy while reducing systemic toxicity in cancer therapy. With operational flexibility, noninvasiveness, and high spatiotemporal resolution, photoactivatable nanomedicines have drawn growing attention. Distinct from traditional controlled release systems relying on the difference of biomarker concentrations between disease and healthy tissues, photoactivatable nanomedicines capitalize on the interaction between nanotransducers and light to either trigger photochemical reactions or generate reactive oxygen species (ROS) or heat effect to remotely induce pharmaceutical actions in living subjects. Herein, the recent advances in the development of photoactivatable protherapeutic nanoagents for oncology are summarized. The design strategies and therapeutic applications of these nanoagents are described. Representative examples of each type are discussed in terms of structure, photoactivation mechanism, and preclinical models. Last, potential challenges and perspectives to further develop photoactivatable protherapeutic nanoagents in cancer nanomedicine are discussed.

Molecular and nanoengineering approaches towards activatable cancer immunotherapy.

Cancer immunotherapy is an emerging treatment strategy that modulates the immune system to fight against cancer. Although several immunotherapeutic agents have been utilized in the clinic for cancer treatment, low patient response rates and potential immune-related adverse events remain two major challenges. With the merits of delivery controllability and modular flexibility, nanomedicines provide opportunities to facilitate immunotherapies for clinical translation in a safe and effective manner. In this review, we discuss the convergence of nanomedicine with immunotherapy with a focus on molecular and nanoengineering approaches towards activatable cancer immunotherapy. These activatable nanoagents exert immunotherapeutic action only in response to internal or external stimuli. This allows them to locally reprogram the tumor microenvironment and activate antitumor immunity while reducing the incidence of immune-related adverse events. The category of activatable immunotherapeutic nanoagents are discussed along with an overview of their clinical translation prospects and challenges.

Transformable hybrid semiconducting polymer nanozyme for second near-infrared photothermal ferrotherapy.

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.