A Porous Organic Framework-Based Nanoplatform for Directional Destruction on Endoplasmic Reticulum to Enhance Tumor Immunotherapy

With the development of oncology, immunotherapy holds great promise for tumor treatment. However, immunogenic cell death (ICD), an important stimulator of immune response, often fails to trigger effective immunotherapy. Herein, a strategy to cause endoplasmic reticulum (ER) stress for further amplifying ICD is reported. A porous organic framework-based nanoplatform (PLGH-T^ER) with good targeting ER ability for chemiluminescence resonance energy transfer (CRET) based-photodynamic therapy (PDT) is developed, which solves the limitations of the restricted penetration of light and suboptimal bioavailability of commonly used photosensitizers (PS). Once accumulated in ER, PLGH-T^ER activates the translation from glucose to H₂O₂ for starvation therapy and further elicit CRET-based-PDT, which results in ER stress and amplified ICD ultimately. Then, the amplified ICD promotes the release of damage-associated molecular patterns , realizing enhanced immunotherapy. Consequently, PLGH-T^ER can achieve directional destruction on ER and inhibit tumor invasion and recurrence, which expands the application of porous organic framework for tumor immunotherapy.     

A Microenvironment Dual-Responsive Nano-Drug Equipped with PD-L1 Blocking Peptide Triggers Immunogenic Pyroptosis for Prostate Cancer Self-Synergistic Immunotherapy

Induction of immunogenic cell death (ICD) in tumor combined with immune checkpoint blockade (ICB) therapy is widely developed to improve the efficacy of cancer immunotherapy. However, the current ICD induced based on apoptosis, i.e., immunogenic apoptosis, is often restricted in immunogenicity owing to the inflammatory quenching that occurs early in apoptosis. Recently, pyroptosis is demonstrated to be a more efficient ICD form, i.e., immunogenic pyroptosis. The cell contents released during pyroptosis can powerfully activate tumor immunogenicity. Herein, first, it is demonstrated that lower doses of epigenetic drug decitabine can increase GSDME expression in prostate cancer (PCa) RM-1 cells and successfully induce an apoptosis-pyroptosis transition after photodynamic therapy (PDT). Subsequently, a microenvironment dual-responsive nano-drug equipped with PD-L1 blocking peptide (TSD@LSN-D) is developed for self-synergistic cancer immunotherapy. The poorly immunogenic RM-1 PCa model confirm that the powerful antitumor immune response evoked by TSD@LSN-D not only can effectively inhibit the primary tumor but also form a long-term immune memory to prevent PCa recurrence and metastasis. To the best of authors’ knowledge, this work presents the first concept that promotes the apoptosis–pyroptosis transition after tumor PDT through epigenetic modulation. Furthermore, the powerful combination of immunogenic pyroptosis with ICB opens a new platform for PCa immunotherapy.     

Single Small Molecule-Assembled Mitochondria Targeting Nanofibers for Enhanced Photodynamic Cancer Therapy In Vivo

Photodynamic therapy (PDT) has emerged as an attractive alternative in cancer therapy, but its therapeutic effects are limited by the nonselective subcellular localization and poor intratumoral retention of small-molecule photosensitizes. Here a fiber-forming nanophotosensitizer (PQC NF) that is composed of mitochondria targeting small molecules of amphiphilicity is reported. Harnessing the specific mitochondria targeting, the light-activated PQC NFs produce approximately 110-fold higher amount of reactive oxygen species in cells than free photosensitizers and can dramatically induce mitochondrial disruption to trigger intense apoptosis, showing 20–50 times better in vitro anticancer potency than traditional photosensitizers. As fiber-shaped nanomaterials, PQC NFs also demonstrated a long-term retention in tumor sites, solving the challenge of rapid clearance of small-molecule photosensitizers from tumors. With these advantages, PQC NFs achieve a 100% complete cure rate in both subcutaneous and orthotopic oral cancer models with the administration of only a single dose. This type of single small molecule-assembled mitochondria targeting nanofibers offers an advantageous strategy to improve the in vivo therapeutic effects of conventional PDT.     

Persistent Luminescence Immune Hydrogel for Photodynamic-Immunotherapy of Tumors In Vivo

Persistent luminescence material (PLM)-based photodynamic therapy (PDT) has shown tremendous promise in tumor elimination via avoiding continuous external light illumination. In addition, the tumor-associated antigens produced by PDT can trigger systemic antitumor immune responses, but only exhibit a limited immunotherapy effect. Herein, a persistent luminescence immune hydrogel is developed via a “turning solid into gel” strategy by introducing a PLM and an immunoadjuvant (R837) into an alginate-Ca²⁺ hydrogel for rechargeable photodynamic-immunotherapy of tumors, for the first time. The designed PLM-R837-ALG hydrogel exhibits the intact persistent luminescence of the PLM, 100% of utilization efficiency of the hydrophobic precursors, good biocompatibility and syringeability, and can be easily injected into tumors to serve as an internal light source for efficiently activating photosensitizers to induce a sustained PDT effect. Moreover, the loaded R837 can significantly amplify the immunogenicity of tumor-associated antigens originating from PL sensitized PDT, thereby leading to a powerful immune response to suppress tumors in vivo. The proposed PL-based photodynamic-immunotherapy provides a novel combined tumor treatment paradigm.     

光动力疗法对Louis肺癌鼠的杀伤及免疫效应

应用光动力疗法对 30只接种Louis肺癌瘤株的昆明小鼠作杀伤实验研究。对实验组与对照组荷瘤鼠抑瘤曲线、抑瘤率及免疫学指标进行检测。结果表明 ,两组肿瘤生长曲线存在明显差异 (P<0 0 5 )。两组肿瘤生长体积和肿瘤重量均存在明显差异 (P <0 0 1)。实验组瘤体积抑制率为 5 2 94 % ,瘤重量抑制率为 37 2 4 %。各免疫指标与对照组差异有显著性。说明光动力疗法对肿瘤细胞具有杀伤和抑制生长作用 ,并且对荷瘤小鼠的免疫功能有调节作用     

Design of Calixarene-Based ICD Inducer for Efficient Cancer Immunotherapy

Immunogenic cell death (ICD), which in situ generates cancer vaccines and elicits protective cognate anticancer immunity, has brought brightness to cancer immunotherapy. However, poor immunogenicity and low response rate of current ICD-inducing strategies restrict the development and clinical application of ICD-based immunotherapy. Herein, a novel calixarene, quaternary ammonium-modified azocalix[4]arene (CA-3) that drive bona fide ICD with high efficiency, is presented. In addition, the unique macrocyclic structure offers CA-3 with great potential to bind with anticancer drugs via host–guest interactions. With these two functions in one molecule, CA-3 effectively cooperates with various chemotherapeutics to improve their anticancer performance by activating ICD-associated anti-tumor immunity. These unique characteristics make CA-3, a general platform for improving the prognosis of many chemotherapies commonly used in clinical practice. Furthermore, the structure-activity relationship established in this study also provides insights for the design and synthesis of more efficient calixarene-based ICD inducers.     

The AIE-Active Dual-Cationic Molecular Engineering: Synergistic Effect of Dark Toxicity and Phototoxicity for Anticancer Therapy

The development of anticancer therapy is significant to human health but remains a huge challenge. Photodynamic therapy (PDT), inducing the synergistic mitochondrial dysfunction in cancer cells is a promising approach but suffer from the low efficiency in hypoxic microenvironment and deep-seated tumors. Herein, to improve the outcomes of PDT for cancer treatment, a series of red fluorophores consisting of dual-cationic triphenylphosphonium-alkylated pyridinium and (substituted) triphenylamine are prepared as organelle-targeting antitumor photosensitizers (PSs) with aggregation-induced emission characteristics. These PSs can selectively accumulate at the mitochondria or lysosomes of cancer cells with both dark- and photo-cytotoxicity, making them possess excellent killing effect on cancer cells and efficient inhibition of tumor growth in living mice. This study brings about new insight into the development of powerful cancer treatment.     

A NIR-II Fluorescent PolyBodipy Delivering Cationic Pt-NHC with Type II Immunogenic Cell Death for Combined Chemotherapy and Photodynamic Immunotherapy

Tumor immunotherapy has emerged as one of the most promising clinical techniques to treat cancer tumors. Despite its clinical application, the cancerous immunosuppressive microenvironment limits the therapeutic efficiency of the treatment. To generate a stronger immunogenic therapeutic effect, herein, a platinum complex for chemotherapy and a BODIPY photosensitizer for photodynamic therapy are encapsulated into multimodal type II immunogenic cell death (ICD) induce nanoparticles. As the platinum complex and the photosensitizer are able to induce type II ICD, an exceptionally strong immune response is observed in triple-negative breast cancer cells. While remaining stable and therefore poorly cytotoxic in the dark, the nanomaterial is found to quickly dissociate upon exposure to near-infrared light, causing a multimodal mechanism of action in cancer cells as well as multicellular tumor spheroids through combined chemotherapy, photodynamic therapy, and immunotherapy. The nanoparticles are found to nearly fully eradicate a triple-negative breast cancer tumor and therefore to strongly enhance the survival of tumor-bearing mice models using low drug and light doses.     

Mitochondria‐Targeted Small‐Molecule Fluorophores for Dual Modal Cancer Phototherapy

Mitochondria are recognized as the ideal target for cancer treatment because they play a central role in oxidative metabolism and apoptosis. In this work, a mitochondria‐targeted near‐infrared (NIR) photosensitizer (PS) for synchronous cancer photodynamic therapy (PDT) and photothermal therapy (PTT) is synthesized. This multifunctional small‐molecule PS is developed from a variety of synthesized heptamethine cyanine dyes, which are modified with various N‐alkyl side chains on the lipophilic cationic heptamethine core. It is demonstrated to preferentially accumulate in cancer cells by organic‐anion transporting polypeptide mediated active transport and retain in mitochondria by its lipophilic cationic property. As mitochondria are susceptible to hyperthermia and excessive reactive oxygen species, this new PS integrating PTT and PDT treatment exhibits highly efficient phototherapy in multiple cancer cells and animal xenograft models. Furthermore, this targeted PS with NIR imaging property also enables tumors and their margins clearly visualized, providing the potential for precisely imaging‐guided phototherapy and treatment monitoring. This is the first report that a small‐molecule PS integrates both cancer PTT and PDT treatment by targeting mitochondria, significantly increasing the photosensitization. This work may also present a practicable strategy to develop small‐molecule‐based cancer theranostic agents for simultaneous cancer targeting, imaging, and therapy.     

光动力疗法对荷瘤鼠杀伤作用的组织形态学实验研究

目的：探讨光动力疗法恶性肿瘤杀伤作用的机制。方法：应用光动力疗法对接种H22肝癌的40只昆明小鼠作肿瘤杀伤的对比实验研究。结果：通过组织形态学和抑瘤检测证实，光动力疗法能选择性杀伤癌细胞。结论：在治疗后24小时内就可以见到癌细胞出现空泡变性、核固缩、溶解、坏死，随着时间推移坏死更加明显。同时还证实这种光动力疗法对正常细胞和组织没有损伤。     

A Triple‐Collaborative Strategy for High‐Performance Tumor Therapy by Multifunctional Mesoporous Silica‐Coated Gold Nanorods

To integrate treatments of photothermal therapy, photodynamic therapy (PDT), and chemotherapy, this study reports on a multifunctional nanocomposite based on mesoporous silica‐coated gold nanorod for high‐performance oncotherapy. Gold nanorod core is used as the hyperthermal agent and mesoporous silica shell is used as the reservoir of photosensitizer (Al(III) phthalocyanine chloride tetrasulfonic acid, AlPcS₄). The mesoporous silica shell is modified with β‐cyclodextrin (β‐CD) gatekeeper via redox‐cleavable Pt(IV) complex for controlled drug release. Furthermore, tumor targeting ligand (lactobionic acid, LA) and long‐circulating poly(ethylene glycol) chain are introduced via host–guest interaction. It is found that the nanocomposite can specifically target to hepatoma cells by virtue of the LA targeting moiety. Due to the abundant existence of reducing agents within tumor cells, β‐CD can be removed by reducing the Pt(IV) complex to active cisplatin drug for chemotherapy, along with the releasing of entrapped AlPcS₄ for effective PDT. As confirmed by in vitro and in vivo studies, the nanocomposite exhibits an obvious near‐infrared induced thermal effect, which significantly improves the PDT and chemotherapy efficiency, resulting in a superadditive therapeutic effect. This collaborative strategy paves the way toward high‐performance nanotherapeutics with a superior antitumor efficacy and much reduced side effects.     

Fluorination-Induced Multi-Enhancement of a Nano-Photosensitizer for Deep Photodynamic Therapy against Hypoxia Tumor

Organic dyes hold great promise for application in photodynamic therapy (PDT). However, they currently face challenges such as inadequate photodynamic activity, limited tumor penetration, and constraints imposed by tumor hypoxia. Here, a facile and efficient strategy is presented for multi-enhanced PDT through the fluorination of a squarylium indocyanine dye-based photosensitizer (FCy). The amphiphilic FCy features perfluorooctane and PEG-biotin moieties conjugated to a squarylium indocyanine core. In aqueous environments, FCy spontaneously self-assembles into stable nano-sized photosensitizers (FCy NPs), demonstrating a high oxygen loading ability attributable to the presence of perfluoroalkyl groups. Consequently, the aggregation of squarylium indocyanine dyes remarkably boosts the photodynamic effect, yielding a 15-fold improvement in singlet oxygen quantum yield. Owing to the perfluoroalkyl group, FCy NPs exhibit increased endoplasmic reticulum (ER)- accumulating abilities, which further induce ER stress upon laser irradiation and enhance the PDT effect. Furthermore, the superior deep tumor penetration ability of FCy NPs is confirmed through both in vitro and in vivo studies. With efficient oxygen supply to the deep tumor regions, FCy NPs demonstrate potent imaging-guided PDT against hypoxia tumors. The study substantiates the enhanced ER-accumulating ability of the perfluoroalkyl group and presents a facile fluorination strategy for the multi-enhancement of photosensitizers.     

Two-Photon Absorption Induced Cancer Immunotherapy Using Covalent Organic Frameworks

Immune checkpoint blockade therapy is revolutionizing the traditional treatment model of multiple tumor types, but remains ineffective for a large subset of patients. Photodynamic therapy (PDT) has been shown to induce cancer cell death and provoke an immune response, and may represent a potential strategy to synergize with immune checkpoint blockade therapy. However, the limited tissue penetration of exciting light for conventional PDT largely hinders its application in the clinic and its further combination with immunotherapy. Here, a serrated packing covalent organic framework (COF), COF-606, with excellent two-photon absorption (2PA) property and photostability, largely avoids aggregation-caused quenching, therefore offering high reactive oxygen species (ROS) generation efficiency; it is used as a 2PA photosensitizer for PDT in deep tumor tissue. COF-606 induced PDT is shown to be efficient in inducing immunogenic cell death, provoking an immune response and normalizing the immunosuppressive status for the first time. This makes it possible to combine 2PA induced PDT using COF with programmed cell death protein 1 immune checkpoint blockade therapy. Such combination leads to strong abscopal tumor-inhibiting efficiency and long-lasting immune memory effects, standing as a promising combinatorial therapeutic strategy for cancer treatment.     

Covalent Organic Framework‐Supported Molecularly Dispersed Near‐Infrared Dyes Boost Immunogenic Phototherapy against Tumors

Photodynamic therapy (PDT) mediated by near‐infrared (NIR) dyes is a promising cancer treatment modality; however, its use is limited by significant challenges, such as hypoxic tumor microenvironments and self‐quenching of photosensitizers. These challenges hamper its utility in inducing immunogenic cell death (ICD) and triggering potent systemic antitumor immune responses. This study demonstrates that molecular dispersion of NIR dyes in nanocarriers can significantly enhance their ability to produce reactive oxygen species and potentiate synergistic PDT and photothermal therapy against tumors. Specifically, NIR dye indocyanine green (ICG) can be spontaneously adsorbed to covalent organic frameworks (COFs) via π–π conjugations to prevent intermolecular stacking interactions. Then, ICG‐loaded COFs are ultrasonically exfoliated and coated with polydopamine (PDA) to construct a new phototherapeutic agent ICG@COF‐1@PDA with enhanced efficacy. In conjunction with ICG@COF‐1@PDA, a single round of NIR laser irradiation can induce obvious ICD, elicit antitumor immunity in colorectal cancer, and yield 62.9% inhibition of untreated distant tumors. ICG@COF‐1@PDA also exhibits notable phototherapeutic efficacy against 4T1 murine breast to lung metastasis, a spontaneous metastasis mode for triple‐negative breast cancers (TNBCs). Overall, this study reveals a novel nanodelivery system for molecular dispersion of NIR dyes, which may present new therapeutic opportunities against primary and metastatic tumors.     

Metabolic Regulation of Tumor Microenvironment with Biohybrid Bacterial Bioreactor for Enhanced Cancer Chemo-Immunotherapy

Immunogenic cell death (ICD) induced by specific chemotherapeutic agents is often hampered by the immunosuppressive tumor microenvironment (TME). Here, a bacterial bioreactor E@Fe-DOX, is developed, to enhance ICD-mediated antitumor immunity by in situ manipulation of tumor metabolism-immune interactions. The E@Fe-DOX bioreactor is constructed by depositing doxorubicin-loaded iron-polyphenol nanoparticles on Eubacterium hallii, which can specifically target hypoxic tumor regions and release doxorubicin and Fe³⁺ to induce ICD. In addition, Eubacterium hallii can continuously convert intratumoral lactate to butyrate, which inhibits the polarization of pro-tumoral M2-like macrophages and improves the function of tumor-infiltrating cytotoxic T cells. Furthermore, E@Fe-DOX promotes the formation of immune cell-aggregated tertiary lymph structures (TLS) to augment ICD-induced antitumor immunity. In murine tumor models, E@Fe-DOX significantly inhibits tumor growth and enhances immune checkpoint blockade (ICB) therapy. Overall, the developed living biomaterial offers a promising strategy to potentiate cancer chemo-immunotherapy by continuously regulating the intratumoral immuno-metabolic microenvironment.     

Versatile Prodrug Nanoparticles for Acid‐Triggered Precise Imaging and Organelle‐Specific Combination Cancer Therapy

Integration of chemotherapy with photodynamic therapy (PDT) has been emerging as a novel strategy for treatment of triple negative breast cancer (TNBC). However, the clinical translation of this approach is hindered by the unwanted dark toxicity due to the “always‐on” model and low tumor specificity of currently approved photosensitizer (PS). Here, the design of a multifunctional prodrug nanoparticle (NP) is described for precise imaging and organelle‐specific combination cancer therapy. The prodrug NP is composed of a newly synthesized oxaliplatin prodrug, hexadecyl‐oxaliplatin‐trimethyleneamine (HOT), an acid‐activatable PS, derivative of Chlorin e6 (AC), and functionalized with a targeting ligand iRGD for tumor homing and penetration. HOT displays much higher antitumor efficiency than oxaliplatin by simultaneously inducing mitochondria depolarizing and DNA cross‐linking. AC is specifically activated in the orthotopic or metastatic TNBC tumor for fluorescence imaging and PDT, while it remains inert in blood circulation to minimize the dark toxicity. Under the guide of acid‐activatable fluorescence imaging, PDT and chemotherapy can be synergistically performed for highly efficient regression of TNBC. Taken together, this versatile prodrug nanoplatform could achieve tumor‐specific imaging and organelle‐specific combination therapy, which can provide an alternative option for cancer theranostic.     

激光一光化治疗的国内外应用研究进展

介绍了弱激光治疗和光动力治疗的机制以及它的研究进展。氦氖激光照射人体血液，可以增加红血球的溶血率，改善血液载氧能力，降低血沉和粘度。光动力治疗肿瘤的临床结果表明，它对早期肿瘤的治愈是有效的，并能保持患者的生活质量。     

Hyaluronidase with pH‐responsive Dextran Modification as an Adjuvant Nanomedicine for Enhanced Photodynamic‐Immunotherapy of Cancer

The condensed tumor extracellular matrix (ECM) consisting of cross‐linked hyaluronic acid (HA) is one of key factors that results in the aberrant tumor microenvironment (TME) and the resistance to various types of therapies. Herein, hyaluronidase (HAase) is modified by a biocompatible polymer, dextran (DEX), via a pH‐responsive traceless linker. The formulated DEX‐HAase nanoparticles show enhanced enzyme stability, reduced immunogenicity, and prolonged blood half‐life after intravenous injection. With efficient tumor passive accumulation, DEX‐HAase within the acidic TME would be dissociated to release native HAase, which afterward triggers the breakdown of HA to loosen the ECM structure, subsequently leading to enhanced penetration of oxygen and other therapeutic agents. The largely relieved tumor hypoxia would promote the therapeutic effect of nanoparticle‐based photodynamic therapy (PDT), accompanied by the reverse of the immunosuppressive TME to boost cancer immunotherapy. Interestingly, the therapeutic responses achieved by the combination of PDT and anti‐programmed death‐ligand 1 (anti‐PD‐L1) checkpoint blockade therapy could be significantly enhanced by pretreatment with DEX‐HAase. In addition to destructing tumors with direct light exposure, a robust abscopal effect is achieved after such treatment, which is promising for tumor metastasis inhibition. The work presents a new type of adjuvant nanomedicine to assist photodynamic‐immunotherapy of cancer, by effective modulation of TME.     

An Iridium (III) Complex Bearing a Donor–Acceptor–Donor Type Ligand for NIR-Triggered Dual Phototherapy

Iridium(III) complexes are an important group of photosensitizers for photodynamic therapy (PDT). This work constructs a donor–acceptor–donor structure-based iridium(III) complex (IrDAD) with high reactive oxygen species (ROS) generation efficiency, negligible dark toxicity, and synergistic PDT and photothermal therapy (PTT) effect under near-infrared (NIR) stimulation. This complex self-assembles into metallosupramolecular aggregates with a unique aggregation-induced PDT behavior. Compared with conventional iridium(III) photosensitizers, IrDAD not only achieves NIR light deep tissue penetration but also shows highly efficient ROS and heat generation with ROS quantum yield of 14.6% and photothermal conversion efficiency of 27.5%. After conjugation with polyethylene glycol (PEG), IrDAD is formulated to a nanoparticulate system (IrDAD-NPs) with good solubility. In cancer phototherapy, IrDAD-NPs preferentially accumulate in tumor area and display a significant tumor inhibition in vivo, with 96% reduction in tumor volume, and even tumor elimination.     

Enhanced Antitumor Efficacy by 808 nm Laser‐Induced Synergistic Photothermal and Photodynamic Therapy Based on a Indocyanine‐Green‐Attached W18O49 Nanostructure

A novel nanoplatform based on tungsten oxide (W₁₈O₄₉, WO) and indocyanine green (ICG) for dual‐modal photothermal therapy (PTT) and photodynamic therapy (PDT) has been successfully constructed. In this design, the hierarchical unique nanorod‐bundled W₁₈O₄₉ nanostructures play roles in being not only as an efficient photothermal agent for PTT but also as a potential nanovehicle for ICG molecules via electrostatic adsorption after modified with trimethylammonium groups on their surface. It is found that the ability of ICG to produce cytotoxic reactive oxygen species for PDT is well maintained after being attached on the WO, thus the as‐obtained WO@ICG can achieve a synergistic effect of combined PTT and PDT under single 808 nm near‐infrared (NIR) laser excitation. Notably, compared with PTT or PDT alone, the enhanced HeLa cells lethality of the 808 nm laser triggered dual‐modal therapy is observed. The in vivo animal experiments have shown that WO@ICG has effective solid tumor ablation effect with 808 nm NIR light irradiation, revealing the potential of these nanocomposites as a NIR‐mediated dual‐modal therapeutic platform for cancer treatment.