In Situ Photocatalyzed Oxygen Generation with Photosynthetic Bacteria to Enable Robust Immunogenic Photodynamic Therapy in Triple‐Negative Breast Cancer

Hypoxia in the tumor microenvironment is a major hurdle dampening the antitumor effect of photodynamic therapy (PDT). Herein, active photosynthetic bacteria (Synechococcus 7942, Syne) are utilized for tumor‐targeted photosensitizer delivery and in situ photocatalyzed oxygen generation to achieve photosynthesis‐boosted PDT. Photosensitizer‐encapsulated nanoparticles (HSA/ICG) are assembled by intermolecular disulfide crosslinking and attached to the surface of Syne with amide bonds to form a biomimetic system (S/HSA/ICG). S/HSA/ICG combined the photosynthetic capability of Syne and the theranostic effect of HSA/ICG. Syne capable of photoautotrophy exhibit a moderate immune stimulation effect and a certain photodynamic role under 660 nm laser irradiation. Upon intravenous injection into tumor‐bearing mice, S/HSA/ICG can effectively accumulate in tumors and generate oxygen continuously under laser irradiation through photosynthesis, which remarkably relieve tumor hypoxia and enhance reactive oxygen species production, thereby completely eliminating primary tumors. This photosynthesis‐boosted PDT can also effectively reverse the tumor immunosuppressive microenvironment and robustly evoke systematic antitumor immune responses, which exhibit excellent effect on preventing tumor recurrence and metastasis inhibition in a metastatic triple‐negative breast cancer mouse model. Hence, this photosynthetic bacteria‐based photosynthesis‐boosted immunogenic PDT offers a promising approach to eliminate both local and metastatic tumors.     

A Bioactive Photosensitizer for Hypoxia-Tolerant Molecular Targeting-Photo-Immunotherapy of Malignant Tumor

Photosensitizers (PSs) with effective reactive oxygen species generation ability against hypoxia are of great potential for clinical treatment of malignant tumors. However, complex tumor microenvironment, such as antioxidative responses and immunosuppression, would ineluctably limit the efficiency of photodynamic therapy (PDT). Herein, a molecular-targeting photosensitizer QTANHOH is rationally designed for histone deacetylases (HDACs-targeting photo-immunotherapy application. The PS QTANHOH displays excellent type-I/II PDT performance, exhibiting significant phototoxicity toward cancer cells with half maximal inhibitory concentration (IC₅₀) less than 10 nm in both normoxia and hypoxia conditions under blue laser irradiation. Moreover, the bioactive compound could inhibit HDACs and activate the immune microenvironment to boost PDT efficacy on the immunocompetent BALB/c mice with breast cancer, leading to the eradication of solid tumor and inhibition of metastasis. Notably, the molecular-targeting photosensitizer introduces an alternative strategy to achieve superior phototherapy for cancer therapy.     

Antibody Engineered Platelets Attracted by Bacteria-Induced Tumor-Specific Blood Coagulation for Checkpoint Inhibitor Immunotherapy

Bacteria can act as a promising anti-tumor platform due to their specific targeting capacity to the tumor microenvironment. In this study, it is discovered that intravenous administration of Escherichia coli TOP10 induces rapid and intense blood coagulation in tumor tissues instead of normal tissues. It is demonstrated that E. coli TOP10 can act as an activator of a coagulation cascade to trigger abnormal hemorrhage, blood coagulation, and inflammation with abundant macrophages recruitment in tumors. In addition, the recruited macrophages are principally polarized by lipopolysaccharide in the bacterial wall to the anti-tumor M1-like phenotype. Based on the above finding, coagulation-tropism blood platelets decorated with CD47 antibodies (Anti-CD47), which possess tropism for bacteria-treated tumors are further prepared. As a result, Anti-CD47 blocks the “don't eat me” signal from tumor cells, consequently promoting the phagocytosis of polarized M1-like phenotype macrophages for tumor cells. This manipulation of local blood coagulation in tumors may find great potential for accurately delivering immune checkpoint inhibitors and facilitating tumor immunotherapy.     

Photosynthetic Biohybrid Nanoswimmers System to Alleviate Tumor Hypoxia for FL/PA/MR Imaging‐Guided Enhanced Radio‐Photodynamic Synergetic Therapy

Biohybrid microswimmers have recently shown to be able to actively perform in targeted delivery and in vitro biomedical applications. However, more envisioned functionalities of the microswimmers aimed at in vivo treatments are still challenging. A photosynthetic biohybrid nanoswimmers system (PBNs), magnetic engineered bacteria‐Spirulina platensis, is utilized for tumor‐targeted imaging and therapy. The engineered PBNs is fabricated by superparamagnetic magnetite (Fe₃O₄ NPs) via a dip‐coating process, enabling its tumor targeting ability and magnetic resonance imaging property after intravenous injection. It is found that the PBNs can be used as oxygenerator for in situ O₂ generations in hypoxic solid tumors through photosynthesis, modulating the tumor microenvironment (TME), thus improving the effectiveness of radiotherapy (RT). Furthermore, the innate chlorophyll released from the RT‐treated PBNs, as a photosensitizer, can produce cytotoxic reactive oxygen species under laser irradiation to achieve photodynamic therapy. Excellent tumor inhibition can be realized by the combined multimodal therapies. The PBNs also possesses capacities of chlorophyll‐based fluorescence and photoacoustic imaging, which can monitor the tumor therapy and tumor TME environment. These intriguing properties of the PBNs provide a promising microrobotic platform for TME hypoxic modulation and cancer theranostic applications.     

Cascade-Responsive “Oxidative Stress Amplifiers” Simultaneously Destroy Lysosomes and Co-Deliver CRISPR/Cas9 to Enhance Oxidative Damage in Tumor

Amplifying intracellular oxidative stress by organelle-targeted reactive oxygen species (ROS) production combined with tumor cell-specific gene disruption is a promising strategy for tumor treatment. However, due to the vulnerability of CRISPR/Cas9 ribonucleoproteins (RNPs) to ROS, co-delivery of CRISPR/Cas9 RNPs and ROS generators to enhance the sensitivity of tumor cells to oxidative stress remains challenging. Herein, a cascade-responsive “oxidative stress amplifier” (named DR-TAF-pHT/FA) is proposed, which can successively respond to cathepsin B, localized laser irradiation and ATP to generate ROS on the lysosomal membrane of tumor cells and release Cas9/sgNrf2 RNPs for efficient gene disruption. It is demonstrated that, under near infrared (NIR) irradiation, DR-TAF-pHT/FA achieves targeted rupture of lysosomal membranes, inducing significant intracellular oxidative stress. Meanwhile, due to the protective function of TAF coating (TA-Fe³⁺ coordination self-assembled networks), Cas9/sgNrf2 RNPs can safely escape into the cytoplasm and be released in response to ATP, further amplifying oxidative stress and promoting tumor cell apoptosis through efficient Nrf2 gene disruption. Treatment with DR-TAF-pHT/FA + NIR significantly improves tumor ablation efficiency and extends median survival time (over 70 days) in Hela xenograft models. This “oxidative stress amplifier” provides a new paradigm for multimodal and synergistic tumor therapy through precise lysosomal membrane bursting together with efficient Nrf2 gene disruption.     

Schottky Heterojunction Realizes In Situ Vaccine-Like Antitumor Efficacy and Microenvironment Remodeling Upon Near-Infrared Laser Response in Cold Tumors

Cold tumor is one of the most refractory tumors due to its low immunogenicity and absence of T cell infiltration. The immunotherapeutic effect of near-infrared (NIR) responsive nanomaterials on tumors is far from satisfactory. Herein, ultrasmall γ-MnO₂ nanodots are anchored on the intrinsic metallic Ti₃C₂(OH)₂, modified with bovine serum albumin, to realize a Schottky heterojunction (labeled as TC-MnO₂@BSA), which can be utilized to reshape the cold tumor microenvironment (TME) through in situ vaccine-like antitumor effect. The Schottky heterojunction endows TC-MnO₂@BSA with improved photothermal conversion and reactive oxygen species (ROS) generation. Excess ROS and heat lead to tumor immunogenic death (ICD) and abundant damaged double-strain DNA releasing into TME, coordinated with TC-MnO₂@BSA-derived Mn²⁺, magnifying the cGAS-STING signaling pathway, eventually promoting antigen presentation of dendritic cells and infiltration of T cells. Such a NIR-activated nanovaccine can achieve complete ablation of tumors while robust activating systemic antitumor immune response. Furthermore, it inhibits the growth of abscopal tumors through dramatically “heating” their cold TME. This work introduces a universal strategy to magnify the photothermal and immune adjuvant effect through the gain of Schottky heterostructure, as a novel paradigm to construct the multifunctional in situ nanovaccine.     

Photothermo-Promoted Nanocatalysis Combined with H2S-Mediated Respiration Inhibition for Efficient Cancer Therapy

Nanocatalytic medicine has emerged as a promising method for the specific cancer therapy by mediating the interaction between tumor microenvironment biomarkers and nanoagents. However, the produced antitumor cell killing molecules, such as reactive oxygen species (ROS), by catalysis are insufficient to inhibit tumor growth. Herein, a novel kind of polyvinyl pyrrolidone modified multifunctional iron sulfide nanoparticles (Fe_1−xS-PVP NPs) is developed via a one-step hydrothermal method, which exhibits high photothermal (PT) conversion efficiency (η = 24%) under the irradiation of 808 nm near-infrared laser. The increased temperature further facilitates the Fenton reaction to generate abundant •OH radicals. More importantly, under an acidic (pH = 6.5) condition within tumor environment, the Fe_1−xS-PVP NPs can in situ produce H₂S gas, which is evidenced to suppress the activity of enzyme cytochrome c oxidase (COX IV) in cancer cells, contributing to inhibit the growth of tumor. Both in vitro and in vivo results demonstrate that the H₂S-mediated gas therapy in combination with PT enhanced ROS achieves excellent antitumor performance, which can open up a new approach for the design of gas-mediated cancer treatment.     

Touchable Electrochemical Hydrogel Sensor for Detection of Reactive Oxygen Species-induced Cellular Senescence in Articular Chondrocytes

In this study, a reactive oxygen species (ROS)-responsive hydrogel sensor (PD/MnO₂ hydrogel) is developed that can efficiently detect senescent cells. Using immature murine articular chondrocytes with serial passages, the sensor can identify small interfering RNA (siRNA) knockdown of peroxisome proliferator-activated receptor-alpha (PPARα) based on the concentration of ROS in cells, simultaneously maintaining its balance via scavenging activity to prevent cartilage degradation in osteoarthritis (OA). The hydrogel sensor exhibits a change in electronic properties, with a distinct resistance from 201.9 kΩ for P0 to 362.9 kΩ for P3, and fluorescence off/on performance with an increase in passaging time. In vitro investigation using PPARα-specific siRNA reveals a correlation between pressure sensitivity and senescent activity, wherein an elevation in observed signal occurred (41.5%). In vivo analysis reveals significant decrease in degradation of the cartilage of both young, 3 months old aged, 18 months old, and PPARα^−/− mice compared to PPARα^+/+ mice based on safranin O stains. The expression level of interleukin-1β is reduced in the cartilage of aged PPARα^−/− mice after implantation with hydrogel, indicating the potential of PD/MnO₂ hydrogel as a therapeutic modality against OA.     

Targeted Magnetic Resonance Imaging/Near-Infrared Dual-Modal Imaging and Ferroptosis/Starvation Therapy of Gastric Cancer with Peritoneal Metastasis

Accurate identification and visualization of peritoneal metastases (PM) are clinically essential to improving the prognosis for gastric cancer. However, owing to the multifocal spread of peritoneal metastasis nodules, small size, and close contact with adjacent organs, identifying and completely removing them during surgery is extremely challenging, resulting in cancer treatment failure and recurrence. This study develops a T₁-weighted magnetic resonance imaging (MRI) contrast agent (FeGdNP)-loaded indocyanine green/glucose oxidase (ICG/GOx) with conjugation of an RGD dimer (RGD2) and acid-labile polymer mPEG (FeGdNP-ICG/GOx-RGD2-mPEG). Compared with commercial Magnevist, the proposed FeGdNP-ICG/GOx-RGD2-mPEG shows a two to three-fold higher tumor ΔSNR in MRI of peritoneal metastasis and subcutaneous animal models. Compared with free ICG, the increased fluorescent signal of FeGdNP-ICG/GOx-RGD2-mPEG allows for the detection of tiny tumor metastatic nodules (<3 mm), and the removal of the peritoneum transplanted tumors. Abundant gluconic acid and H₂O₂ are generated during the GOx-mediated glucose depletion process in cancer cells, thereby enhancing Fenton reaction efficiency. Accumulated toxic ·OH can damage the mitochondrial function and induce the release of mitochondrial reactive oxygen species, which activates the ferroptosis pathway. The data indicate the potential of the nanoparticles for MRI preoperative diagnosis, intraoperative fluorescence-guided navigation, and ferroptosis tumor therapy.     

Sustained Antitumor Immunity Based on Persistent Luminescence Nanoparticles for Cancer Immunotherapy

Immunotherapy holds great promise for cancer treatment. The key to improving the therapeutic effect is to drive the patient's own immune system to produce a strong, effective, and enduring tumor-specific immune response. Engineered nanoplatforms show promising potential in strengthening antitumor immune responses. However, current nanotherapeutic platforms based on exogenous responses stimulate the immune system only in a transitory and limited manner, which translates into insufficient immune activation and a low therapeutic efficacy. A novel targeted nano-immunostimulant (ZGS-Si-Pc@HA) is fabricated by coupling persistent luminescence nanoparticles with a photosensitizer and hyaluronic acid for sustained immune stimulation upon irradiation with biological window (659 nm) light. ZGS-Si-Pc@HA persistently drives reactive oxygen species production to induce immunogenic cell death, causing a durable tumor-specific immune response. Upon intratumoral injection, ZGS-Si-Pc@HA effectively alleviates immune tolerance and promotes T lymphocyte tumor infiltration. Further, ZGS-Si-Pc@HA enhances the therapeutic effect of checkpoint blockade immunotherapy, effectively inhibiting bilateral tumor growth and triggering an immunological memory effect. Nano-immunostimulants not only provide a new way to boost cancer immunotherapy, but also offer a reliable strategy for fighting cancer metastasis and recurrence clinically.     

Combination of Bacterial‐Photothermal Therapy with an Anti‐PD‐1 Peptide Depot for Enhanced Immunity against Advanced Cancer

Photothermal therapy (PTT) is a promising cancer treatment, but it has so far proven successful only with relatively small subcutaneous tumors in animal models. Treating larger tumors (≈200 mm³) is challenging because most PTT materials do not efficiently reach the hypoxic, avascular center of tumors, and the immunosuppressive tumor microenvironment prevents T cells from fighting against residual tumor cells, thereby allowing recurrence and metastasis. Here, the widely used PTT material polydopamine is coated on the surface of the facultative anaerobe Salmonella VNP20009, which can penetrate deep into larger tumors. The coated bacteria are intravenously injected followed by near‐infrared laser irradiation at the tumor site, combined with a local inoculation of phospholipid‐based phase separation gel containing the anti‐programmed cell death‐1 peptide AUNP‐12. The gel releases AUNP‐12 sustainably during 42 days, maintaining the tumor microenvironment as immunopermissive. Using a mouse model of melanoma, this triple combination of biotherapy, PTT, and sustainable programmed cell death‐1 (PD‐1) blockade shows high efficiency on eliciting robust antitumor immune responses and eliminating relatively large tumors in 50% of animals within 80 days. Thus, the results shed new light on a previously unrecognized immunological facet of bacteria‐mediated therapy, and this innovative triple therapy may be a powerful cancer immunotherapy tool.     

In Situ Exfoliated,N‐Doped,and Edge‐Rich Ultrathin Layered Double Hydroxides Nanosheets for Oxygen Evolution Reaction

The number of catalytically reactive sites and their intrinsic electrocatalytic activity strongly affect the performance of electrocatalysts. Recently, there are growing concerns about layered double hydroxides (LDHs) for oxygen evolution reaction (OER). Exfoliating LDHs is an effective method to increase the reactive sites, however, a traditional liquid phase exfoliation method is usually very labor‐intensive and time‐consuming. On the other hand, proper heteroelement doping and edge engineering are helpful to tune the intrinsic activity of reactive sites. In this work, bulk CoFe LDHs are successfully exfoliated into ultrathin CoFe LDHs nanosheets by nitrogen plasma. Meanwhile, nitrogen doping and defects are introduced into exfoliated ultrathin CoFe LDHs nanosheets. The number of reactive sites can be increased efficiently by the formation of ultrathin CoFe LDHs nanosheets, the nitrogen dopant alters the surrounding electronic arrangement of reactive site facilitating the adsorption of OER intermediates, and the electrocatalytic activity of reactive sites can be further tuned efficiently by introducing defects which increase the number of dangling bonds neighboring reactive sites and decrease the coordination number of reactive sites. With these advantages, this electrocatalyst shows excellent OER activity with an ultralow overpotential of 233 mV at 10 mA cm^?2.     

Bacterial Outer Membrane-Coated Mesoporous Silica Nanoparticles for Targeted Delivery of Antibiotic Rifampicin against Gram-Negative Bacterial Infection In Vivo

The efficacy of conventional antibiotics therapeutics has declined rapidly due to the emerged antibiotic resistance. There is an urgent need to develop novel approaches to address the problem of antibiotic shortage, particularly for Gram-negative bacteria. Herein, a biomimetic nanodelivery system is proposed to enhance the bacterial targeting and uptake of rifampicin (Rif), a traditional antibiotic but not effective against Gram-negative bacteria. The biomimetic nanodelivery system (Rif@MSN@OMV) is composed of outer membrane vesicles (OMVs) isolated from E. coli as shell and rifampicin-loaded mesoporous silica nanoparticles (MSNs) as core. The OMVs greatly improve the uptake of MSNs in E. coli, but not in Gram-positive bacteria S. aureus, owing to the homotypic targeting function of the OMVs. The Rif@MSN@OMV exhibits enhanced antimicrobial activity against E. coli and completely eradicates bacteria at an equivalent rifampicin concentration (4 µg mL⁻¹) while free rifampicin shows weak bactericidal activity. Meanwhile, the Rif@MSN@OMV maintains good biocompatibility both in vitro and in vivo. More importantly, the Rif@MSN@OMV elevates survival rate of infected mice and reduces bacterial load in intraperitoneal fluid and organs. Overall, the OMVs-coated nanodelivery system provides a novel strategy to improve the antimicrobial efficacy of conventional antibiotic or repurpose drugs for treatment of Gram-negative bacterial infections.     

Sono/Photodynamic Nanomedicine-Elicited Cancer Immunotherapy

Immunotherapy (e.g., cancer vaccines and checkpoint blockades), harnessing the host immune system to recognize and eradicate tumors, has emerged as one of the most potent cancer therapies. The clinical applications of cancer immunotherapies, however, have been limited by their low response rates and immune-related adverse effects. In recent years, sono/photodynamic nanomedicines (SPNs) have received increasing attention for cancer therapy since they have been reported to mediate enhanced immunotherapy by generating reactive oxygen species under site-specific exposure to exogenous energy sources. In particular, SPNs are capable of eliciting immunogenic cancer cell death, leading to the release of tumor-associated antigens and damage-associated molecular patterns. This allows for the maturation of antigen-presenting cells, thus eliminating disseminated or metastatic tumor cells by cytotoxic CD8⁺ T cells. Such immunostimulatory features of SPNs provide opportunities to enhance therapeutic potential by amplifying anticancer immunity when combined with conventional immunotherapeutics, including immune checkpoint inhibitors. This review elaborates on the recent strategies and efforts undertaken by researchers to enhance SPN-elicited cancer immunotherapy. The challenging issues and opportunities for SPNs in the activation of innate or adaptive immune responses and regulation of the tumor immunosuppressive microenvironment are also described.     

NIR Emissive Functional Nanoparticles Promote Precise Pancreatic Cancer Therapy by Co-Targeting Mutant p53 and Oncogenic KRAS

Pancreatic ductal adenocarcinoma (PDAC) presents a formidable global health challenge. Targeting genetic aberrations, particularly KRAS and TP53 mutations, remains a critical challenge in PDAC treatment. Herein, it is demonstrated for the first time that electron-rich aromatic pyrrole derivatives can be transformed into red-to-near-infrared emissive radical cations in an acidic buffer, efficiently targeting mitochondria and triggering mutant p53 (mutp53) degradation. Leveraging the positive charge characteristic of radical cations (P6 ^•+ ), a bifunctional nanoparticle is successfully engineered by combining P6 ^•+ with KRAS siRNA. P6@siKRAS simultaneously induces mutp53 degradation and the oncogenic KRAS downregulation, thereby abrogating gain-of-function effects by mutp53 and inhibiting downstream signaling pathways regulated by KRAS, leading to significant suppression of tumor growth, invasion, and drug resistance. Consequently, P6@siKRAS demonstrates remarkable therapeutic efficacy in both the p53-KRAS-double-mutated pancreatic cancer model and the LSL-Kras^G12D/+; LSL-Trp53^R172H/+; Pdx-1-Cre (KPC) mice model. Moreover, the down-regulation of mutp53 and KRAS by P6@siKRAS not only inhibits tumor growth but also substantially remodels the tumor microenvironment, recruiting and boosting the infiltration of anti-tumor immune cells, thereby augmenting the anti-tumor immune response. This study showcases the development of mutp53-degrading functional gene carriers, offering a promising and innovative therapeutic strategy for tackling p53-KRAS-double-mutated pancreatic cancer.     

Rigid Shell Decorated Nanodevice with Fe/H2O2 Supply and Glutathione Depletion Capabilities for Potentiated Ferroptosis and Synergized Immunotherapy

The overexpressed glutathione peroxidase4 (GPX4) and insufficient H₂O₂ in tumor cells weaken ferroptosis therapy and the elicited anticancer immune response. Herein, a rigid metal-polyphenol shell decorated nanodevice ssPPE_Lap@Fe-TA is constructed to successfully overcome the drawbacks of ferroptosis therapy. The ssPPE_Lap@Fe-TA consists of a rigid Fe-TA network-based shell and disulfide-containing polyphosphoester (ssPPE) core with β-lapachone loading. The rigid Fe-TA network-based shell of ssPPE_Lap@Fe-TA enables its efficient internalization by tumor cell and then disintegrates in the acidic endosome/lysosome to initiate Fe³⁺/Fe²⁺ conversion-driven ferroptosis. The ssPPE core will deplete glutathione (GSH) via the disulfide-thiol exchange reaction to inactivate GPX4, and also trigger the release of β-lapachone to significantly increase intracellular H₂O₂ and then promote Fe³⁺-mediated Fenton reaction, eventually achieving strong inhibition of tumor progression. Moreover, ssPPE_Lap@Fe-TA elicites a robust systemic antitumor immune response by promoting dendritic cells (DCs) maturation and T cell infiltration, and synergizes with anti-PD-L1 antibody (a-PD-L1) to strikingly suppress 4T1 tumor growth and lung metastasis.     

Significant Role of Al in Ternary Layered Double Hydroxides for Enhancing Electrochemical Performance of Flexible Asymmetric Supercapacitor

The Al effect on the electrochemical properties of layered double hydroxides (LDHs) is not properly probed, although it is demonstrated to notably promote the capacitive behavior of LDHs. Herein, ternary NiCo₂Al_x layered double hydroxides with varying levels of Al stoichiometry are purposely developed, grown directly on mechanically flexible and electrically conducting carbon cloth (CC@NiCo₂Al_x‐LDH). Al plays a significant role in determining the structure, morphology, and electrochemical behavior of NiCo₂Al_x‐LDHs. At an increasing level of Al in NiCo₂Al_x‐LDHs, there is a steady evolution from 1D nanowire to 2D nanosheets. The CC@NiCo₂Al‐LDH at an appropriate level of Al and with the nanowire–nanosheet mixed morphology exhibits both significantly enhanced electrochemical performance and excellent structural stability, with about a 2.3‐fold capacitance of NiCo₂‐OH. When applied as the anode in a flexible asymmetric supercapacitor (ASC), the CC@NiCo₂Al‐LDH gives rise to a remarkable energy density of 44 Wh kg^?1 at the power density of 462 W kg^?1, together with remarkable cyclic stability with 91.2% capacitance retention over 15 000 charge–discharge cycles. The present study demonstrates a new pathway to significantly improve the electrochemical performance and stability of transition metal LDHs, which are otherwise unstable in structure and poorly performing in both rate and cycling capability.     

Multivalent Glycosheets for Double Light–Driven Therapy of Multidrug‐Resistant Bacteria on Wounds

With the evergrowing threat posed by multidrug resistance of bacteria, the development of effective antibacterial agents remains a global challenge. Infection with multidrug‐resistant bacteria in hospitals significantly impairs the healing of wounds caused by deep‐burn injuries or diabetic foot ulceration, leading to a high mortality rate among these patients. A multivalent glycosheet for the double light–driven therapy against multidrug‐resistant Pseudomonas aeruginosa (P. aeruginosa) infection on wounds is developed here. Galactose‐ and fucose‐based ligands are self‐assembled to form a glyco‐layer on the surface of thin‐layer molybdenum disulfide, producing the glycosheets capable of selectively localizing P. aeruginosa through multivalent carbohydrate–lectin interactions. The glycosheets loaded with antibiotics have proven applicable for: 1) near‐infrared‐light driven, in situ thermal release of antibiotics, increasing bacterial membrane permeability, and 2) white light–driven reactive‐oxygen‐species production to more thoroughly kill the bacteria. The targetability, together with the light sensibility, of the glycosheets enables a highly effective and optically controlled therapeutic regime for the healing of wounds infected by multidrug‐resistant as well as clinically isolated P. aeruginosa.     

Biodegradable Polymeric Nanoparticles Containing an Immune Checkpoint Inhibitor (aPDL1) to Locally Induce Immune Responses in the Central Nervous System

Immunotherapy is an efficient approach to clinical oncology. However, the immune privilege of the central nervous system (CNS) limits the application of immunotherapeutic strategies for brain cancers, especially glioblastoma (GBM). Tumor resistance to immune checkpoint inhibitors is a further challenge in immunotherapies. To overcome the immunological tolerance of brain tumors, a novel multifunctional nanoparticle (NP) for highly efficient synergetic immunotherapy is reported. The NP contains an anti-PDL1 antibody (aPDL1), upconverting NPs, and the photosensitizer 5-ALA; the surface of the NP is conjugated with the B1R kinin ligand to facilitate transport across the blood-tumor-barrier. Upon irradiation with a 980 nm laser, 5-ALA is transformed into protoporphyrin IX, generating reactive oxygen species. Photodynamic therapy (PDT) further promotes intratumoral infiltration of cytotoxic T lymphocytes and sensitizes tumors to PDL1 blockade therapy. It is demonstrated that combining PDT and aPDL1 can effectively suppress GBM growth in mouse models. The proposed NPs provide a novel and effective strategy for boosting anti-GBM photoimmunotherapy.     

Immunotherapeutic Hydrogel with Photothermal Induced Immunogenic Cell Death and STING Activation for Post-Surgical Treatment

Post-surgical tumor recurrence remains a major clinical concern for patients with malignant solid tumors. Herein, an immunotherapeutic hydrogel (SA_PBA/ZMC/ICG) is developed by incorporating metal ion-cyclic dinucleotide (CDN) nanoparticles (Zn-Mn-CDN, ZMC) and a photosensitizer (indocyanine green, ICG) into phenylboronic acid (PBA)-conjugated sodium alginate (SA_PBA) for photothermal therapy (PTT)-triggered in situ vaccination to inhibit post-surgical recurrence and metastasis of malignant tumors. The gelation of SA_PBA/ZMC/ICG in the residual tumors can achieve accurate local PTT and the local sustained release of CDN and Mn²⁺ with minimal detrimental off-target toxic effects. Furthermore, CDN, which is an agonist of the stimulator of interferon genes (STING), along with Mn²⁺ can activate the STING pathway and trigger type-I-IFN-driven immune responses against tumors. Therefore, the immunotherapeutic hydrogel with enhanced immune response by STING agonist and PTT-induced immunogenic cell death (ICD) reprograms the post-surgical immunosuppressive microenvironment, substantially decreasing the post-surgical recurrence and metastasis of solid tumors in multiple murine tumor models when administered during surgical resection. Taken together, PTT-triggered and STING-mediated in situ cancer vaccination is an effective therapeutic intervention for post-surgical recurrence and metastasis of tumors.