2599 Background: For vaccine design, an antigen and an adjuvant are necessary for an effective immune response. In the context of therapeutic tumor vaccination, in situ vaccination has garnered increasing attention as it enables tumors to provide antigens through radiotherapy or intra-tumoral (i.t.) delivery of immunomodulators. BM201, a selective TLR7/8 agonist uniquely designed for intra-tumoral (i.t.) administration, aims to effectively activate antigen-presenting cells and enhance immunogenicity through combination with radiotherapy by more effectively presenting the tumor antigens exposed to T cells. When combined with intravenous (i.v.) infusion of αPD-1 monoclonal antibody (mAb), it relieves tumor immunosuppression and exerts synergistic anti-tumor effects. Methods: This is an open-label, exploratory, and phase I/IIT study. Phase I portion was a dose-escalation study designed to investigate BM201 (dose range: 24-240mg, i.t. every 2 weeks) in combination with hypofractionated radiotherapy (5-8Gy, 4 fractions) (R-ISV-BM201) in patients with refractory or metastatic solid tumors. Phase IIT portion was designed to investigate BM201 (dose range: 24-240mg, i.t. every 3 weeks) in combination with hypofractionated radiotherapy (5-8Gy, 4 fractions) plus αPD-1 (200mg, i.v. every 3 weeks) (R-ISV-BM201 + αPD-1) in patients with refractory or metastatic soft tissue sarcomas. Primary objective of both 2 studies was safety and tolerability. Secondary endpoints included PK and preliminary anti-tumor activity according to RECIST 1.1 in Phase I, while anti-tumor activity according to irRECIST 1.1 in Phase IIT. Results: Till December 05, 2025, 29 patients had been treated with BM201 (19/29 in Phase I, 10/29 in Phase IIT). Among the 29 patients, 51.7% had been unresponsive to immunotherapy (prior αPD-1). Plasma exposure increased with dose. A sustained-release PK characteristic was observed in most patients experiencing tumor shrinkage. Abscopal effects were observed in 31.6% (6/19) and 50% (5/10) of patients in Phase I and Phase IIT, respectively. In Phase I, the objective response rate (ORR) was 5.2%, and the disease control rate (DCR) was 84.2%; while these were 10.5% and 84.2% in injected lesions. In Phase IIT, the ORR was 20%, and the DCR was 100.0%; while these were 46.1% and 92.3% in injected lesions. The median progression-free survival was 7.7 months, the median overall survival was 17.0 months, and the median duration of response in injected lesions was 5.6 months. The majority of TRAEs were grade 1-2. Grade 3-4 TRAEs mainly included lymphocytopenia, anemia, thrombocytopenia, and hypertension. No grade 5 TRAEs or dose-limiting toxicity was observed. Conclusions: R-ISV-BM201 has a manageable safety profile and has shown encouraging anti-tumor activity. A trigger systemic immune response would be expected when it is synergized with αPD-1 mAb. Clinical trial information: Phase I: NCT06368960 ; Phase IIT: ChiCTR2300077953.

Transdermal vaccines, leveraging the abundant antigen-presenting cells (APCs) resident in the skin to elicit antigen-specific immune responses, have progressed rapidly in recent years. However, successful transdermal vaccines still require effective transdermal delivery systems with potent immune adjuvant functions. Herein, we discovered that bacterial membrane vesicles (BMVs) with unique transdermal penetration behaviors and inherent immune-stimulating abilities could act as a nanoscale platform to engineer transdermal vaccines. In our system, BMVs produced from VNP20009 exhibited superior skin penetration compared to mammalian cell-derived membrane vesicles (CMVs) owing to their marked advantage in paracellular transport. Cholesterol-modified antigenic peptides are then incorporated into the lipid bilayer of BMVs to form a transdermal nanoscale vaccine, in which BMVs serve simultaneously as a transdermal carrier and an adjuvant. Notably, such BMV-based vaccine stimulated dendritic cell (DC) maturation and facilitated antigen cross-presentation, thereby promoting antigen-specific T-cell immunity. After topical application, tumor-antigen-loaded BMVs trigger robust anti-tumor immune responses and achieve efficient protective effects against melanoma tumors. This work highlights the potential of BMVs as a simple yet robust platform to develop transdermal vaccines.

Active initiation of plasma membrane rupture represents a promising strategy to disrupt cellular homeostasis and induce cancer cell death. This study proposes phospholipase A1 (PLA1) as a molecular “cell‐puncher” to hydrolyze phospholipids, compromising cancer cell membrane integrity and enabling uncontrolled molecular flux. PLA1 synergistically enhances the tumoradical efficacy of cholesterol oxidases (CODs) and lipoxygenases (LOXs) by liberating their respective substrates, cholesterol, and polyunsaturated fatty acids. When localized within tumors using a thermoresponsive chitosan/β‐glycerol‐phosphate hydrogel, PLA1‐COD or PLA‐LOX enzymatic pairs achieved effective treatment of CT26 murine tumors through cascading plasma membrane rupture and oxidative stress amplification. Furthermore, the hydrogel‐embedded enzyme system functioned as an injectable embolic agent, suppressing orthotopic N1S1 hepatoma in rats via transcatheter arterial enzyme embolization. This work demonstrated an enzyme‐based oncolytic strategy that targets membrane integrity and oxidative stress pathways, showing significant potential for clinical translation in solid tumor management.

Combining targeted radionuclide therapy (TRT) with immunotherapy offers a potent strategy to amplify antitumor immunity, yet the development of adaptable delivery platforms remains a challenge. Herein, we report a programmable, "plug-and-play" nanoplatform, termed TRT@LnOMVs, engineered for synergistic radio-immunotherapy. By displaying lanmodulin (LanM) on the surface of outer membrane vesicles (OMVs)-derived from attenuated Salmonella typhimurium, this platform enables the versatile and high-efficiency radiolabeling of diverse therapeutic radioisotopes under mild conditions, circumventing the limitations of conventional chelator-based methods. The platform's modularity is further demonstrated by the facile incorporation of lipid-conjugated ligands for precision targeting. In a head-to-head comparison with clinically approved 177Lu-PSMA-617 (Pluvicto), PSMA-targeted TRT@LnOMVs achieved a 90% survival rate in a prostate cancer model, far surpassing the 25% survival rate of Pluvicto. Single-cell RNA sequencing and transcriptomic analysis revealed that TRT@LnOMVs significantly remodeled the tumor immune microenvironment. This occurred through reprogramming immunosuppressive myeloid compartments (including neutrophil subsets and macrophages), expanding cytotoxic CD8+ T and NK cell infiltration, and activating innate immunity to trigger robust antitumor responses. Collectively, TRT@LnOMVs represent a versatile class of biohybrid therapeutics, offering a robust paradigm for next-generation radio-immunotherapy.

Chimeric antigen receptor (CAR)-T cell therapy while demonstrating remarkable efficacies in treating hematologic malignancies, has encountered challenges in solid tumor treatment, partly due to the limited intratumoral infiltration of effective immune cells and thus inefficient interactions between different immune cell types inside those tumors. Herein, we develop an injectable scaffold based on hydrogel microparticles (HMPs) with opposite charges to replicate tertiary lymphoid structures (TLSs) within the tumor microenvironment. With encapsulation of immune-stimulating cytokines inside HMPs and loading of both T cells and B cells between HMPs in the scaffold, the artificial TLSs after intratumoral injection could not only serve as a depot of immunostimulants, but also promote intercellular interactions between B and T lymphocytes to support continuous T cell expansion and activation. As demonstrated in several tumor models, our artificial TLSs loaded with both CAR-T cells and B cells after intratumoral injection could not only effectively suppress local tumors, but also present remarkable abscopal effects to inhibit distant tumors, presenting greatly enhanced therapeutic performance compared to conventional CAR-T therapy. Our work thus presents a novel strategy to improve the efficacy of T-cell-therapies against solid tumors based on immune-activating cell-loaded injectable hydrogel scaffold as artificial TLSs.

Intracellular polyamine metabolic homeostasis is closely linked to therapeutic outcomes in cancer. However, their intrinsic antitumor mechanisms have not been fully clarified. Herein, we demonstrate that the catabolism of spermine (Spm) and spermidine (Spd) mediated by polyamine oxidase directly generates two potent cytotoxic metabolites, namely acrolein and hydrogen peroxide. These metabolites act synergistically to trigger a marked elevation in intracellular reactive oxygen species (ROS), which in turn activate the caspase-1/GSDMD and caspase-3/GSDME signaling pathways, ultimately driving tumor cells into pyroptosis. Based on these findings, we develop a phenylboronic acid-functionalized sodium alginate-based hydrogel controlled-release system (Alg-PBA/Spd). This platform achieves sustained Spd release through coordination interactions and markedly inhibits tumor growth by inducing pyroptosis. Further studies demonstrate that the Alg-PBA/Spd hydrogel synergizes with radiotherapy (RT) to enhance radiosensitivity in an orthotopic breast cancer model and inhibit pulmonary metastasis. Moreover, this hydrogel enables co-delivery of αPD-L1 with sustained release, which significantly improves the response rate of immune checkpoint blockade therapy by inducing pyroptosis and remodeling the tumor immune microenvironment. Overall, this study not only elucidates a previously unrecognized mechanism underlying polyamine metabolism-driven pyroptosis but also offers a versatile platform to enhance the efficacy of RT and immunotherapy.

Cefazolin (CZO) is a first-line prophylactic antibiotic used during the perioperative period; however, upregulation of bacterial efflux pump expression accelerates the development of CZO resistance. This study developes a nanoantibiotic (Cu-CZO) that employs a “reverse Trojan horse” strategy to combat antimicrobial-resistant bacterial infections. Disguised as a “Trojan horse” for CZO in this reverse Trojan horse approach, Cu-CZO disrupts the bacterial copper transport system, leading to downregulation of the CopA transporter. This suppresses copper efflux and inhibits the active efflux of CZO, culminating in the intracellular accumulation of Cu-CZO. This study demonstrates that Cu-CZO effectively accumulates within bacteria and eradicates methicillin-resistant Staphylococcus aureus (MRSA)-induced subcutaneous abscesses. Furthermore, it significantly enhances tissue regeneration and functional recovery in infected wounds. This nanoantibiotic overcomes the key resistance mechanism of active CZO efflux in antimicrobial-resistant bacteria, thereby presenting a novel paradigm for fundamentally addressing antibiotic resistance and extending the clinical lifespan of existing antibiotics.

Oncolytic bacteria have emerged as a promising platform for targeted cancer therapy owing to their intrinsic ability to preferentially colonize tumor tissues, induce direct tumor cell killing, and remodel the tumor microenvironment to activate antitumor immunity. However, native bacteria alone rarely meet the requirements of precision oncology, particularly in terms of spatial specificity, temporal control, and safety. Recent advances in synthetic biology have enabled the construction of stimulus-responsive gene circuits that confer programmable control over therapeutic gene expression in tumor-colonizing bacteria by coupling defined exogenous triggers or endogenous tumor-associated cues to tightly regulated genetic programs. These engineered systems support the tumor-specific delivery of diverse therapeutic payloads, including cytotoxic agents, cytokines, immunomodulatory ligands, prodrug-converting enzymes, metabolic modulators, and nucleic acid-based therapeutics, while minimizing off-target activity. This review thus summarizes recent developments in stimulus-responsive oncolytic bacteria, highlights key design principles and performance trade-offs, and discusses emerging strategies to advance bacteria as programmable living therapeutics for cancer treatment.

Deep brain stimulation (DBS) is effective for treating neurological and psychiatric disorders. However, its tethered configuration, invasiveness, and limited tissue compatibility motivate wireless, minimally invasive alternatives. Here, we develop an in situ-gelled injectable conductive hydrogel (ICH), enabling wireless neuromodulation via electric-field localization under volume conduction. The ICH forms in vivo through bio-catalyzed polymerization and electrostatic self-assembly, yielding a stable, highly conductive, tissue-soft, and biocompatible network. Under high-frequency capacitive coupling, impedance difference between the ICH and surrounding brain tissue induces interfacial polarization and charge accumulation, locally concentrating the electric field to activate nearby neurons. This mechanism is supported by enhanced calcium signaling, increased c-Fos expression, and electrophysiological evidence of balanced basal ganglia-cortical activity. In a Parkinson's disease rat model, ICH-mediated stimulation improved locomotor behavior, preserved dopaminergic neurons, and restored functional connectivity and structural integrity as revealed by fMRI. This injectable hydrogel bioelectronics provides a platform for minimally invasive, wireless neuromodulation therapies.

Mucosa, a vital interface between the body and external environment, often suffers from reactive oxygen burden within its microenvironment, leading to various mucosal inflammatory diseases. Drug delivery directly to inflamed mucosal regions offers a promising therapeutic approach, yet efficacy is compromised by inherent physiological clearance mechanisms. Herein, we developed a covalent mucoadhesive nanoantioxidant self-assembled by a cysteine-modified short peptide (CR8L10) and catalase (CAT) for the treatment of mucosal inflammatory diseases. The obtained CR8L10@CAT nanocomplexes with a cysteine-decorated surface enable robust mucoadhesion by forming dynamic disulfide bonds with mucin-rich mucosa, leading to significantly enhanced CAT retention. Upon intravesical instillation, CR8L10@CAT with improved urine-resistant bladder retention, could be used to treat hard-to-manage interstitial cystitis/bladder pain syndrome (IC/BPS). Notably, intravesically administered CR8L10@CAT effectively eliminated excessive reactive oxygen species (ROS) in the bladder mucosa, thereby inhibiting pro-inflammatory responses, restoring urothelial integrity, and alleviating pain and voiding dysfunction, demonstrating significantly better analgesic effects and superior functional improvement than clinically used intravesical agents. Additionally, inhalation of the mucoadhesive CR8L10@CAT nanoantioxidant also showed enhanced pulmonary retention to effectively mitigate ROS-associated inflammation in treating acute lung injury (ALI). This mucoadhesive CR8L10@CAT nanoantioxidant represents an effective therapeutic strategy to manage different mucosal inflammatory diseases, holding great promise for clinical translation.

Aberrant redox homeostasis owing to overproduction of reactive oxygen species (ROS) within the ocular microenvironment is critically implicated in the pathogenesis of various inflammatory ocular disorders or injuries. Previously reported antioxidant strategies, such as small-molecule ROS scavengers or nano-enzymes, are challenged by rapid tear turnover. Herein, we demonstrate that by decomposing hydrogen peroxide, the most stable form of ROS, catalase (CAT) shows superior ability in mitigating oxidative stress compared to the widely-applied antioxidant enzyme superoxide dismutase (SOD), and is able to effectively clear different types of ROS to restore redox homeostasis. We then developed a thiolation strategy for CAT, and the obtained CAT-SH could form cleavable disulfide bonds with mucins on the ocular surface to allow greatly prolonged retention and sustained ROS scavenging. Such CAT-SH eyedrop treatment significantly improves prognosis in acute corneal alkali burn model, and demonstrates compelling efficacy in treating allergic conjunctivitis by effectively stabilizing mast cells and attenuating allergic responses. In both models, CAT-SH eyedrops offer improved therapeutic performances compared to respective clinically used eyedrop therapies. Meanwhile, such CAT-SH eyedrops exhibit exceptional safety profiles. Our work thus offers a highly promising yet simple eyedrop therapy to treat ocular surface injuries or inflammatory diseases with significant translational potential.

Hyperthermic intraperitoneal chemotherapy (HIPEC) is widely performed for treating peritoneal malignancies, yet its clinical application remains limited by insufficient efficacies and risks in chemotherapy-associated side effects. This study demonstrates that mild hyperthermia enhances cancer cell sensitivity to hydrogen peroxide (H2O2) and Ca2+ exposure while sparing normal cells at both elevated and physiological temperatures. Mechanistically, mild hyperthermia promotes H2O2 cellular entry, synergistically activating calcium channels in the plasma membrane and endoplasmic reticulum to induce Ca2+-overload-dependent cancer cell necroptosis. Using H2O2 and Ca2+ solution as a thermo-sensitive necroptosis-inducing perfusate (TNIP), peritoneal perfusion at 43°C demonstrates stronger suppressive effects on the growth of multiple peritoneal tumors in mice compared to conventional HIPEC using various chemotherapeutics. TNIP-mediated hyperthermic intraperitoneal treatment also elicits robust antitumor immunity in syngeneic murine models, with enhanced therapeutic efficacy when combined with postoperative immune checkpoint blockade therapy. The superior immune activation capacities of this strategy are further validated in patient-derived organoids. This work establishes a chemo-free, thermo-activated immunogenic perfusion strategy to selectively trigger cancer cell necroptosis, demonstrating a translatable hyperthermic intraperitoneal immunotherapy with improved therapeutic efficacy and safety.

Hepatic arterial infusion chemotherapy (HAIC) delivers high local drug concentrations for hepatoma treatment but faces challenges such as catheter-related complications and systemic toxicity. To address these, we developed Mel-gel, an ultrasound-driven hydrogel system formed entirely by the chemotherapeutic agent Melphalan (Mel) without chemical modifications. Under ultrasound, Mel transitions from spherical to worm-like aggregates, rapidly forming a nanofiber-based hydrogel through non-covalent interactions. This innovative system offers sustained drug release, excellent bioavailability, and improved biosafety profiles. Mel-gel enables expedited catheter removal, reduces systemic toxicity, enhances local drug concentration, and prolongs drug-cell interaction time. Compared to conventional HAIC systems, Mel-gel’s unique in situ formation maximizes drug delivery and achieves superior targeting within complex vascular structures. In a rat orthotopic hepatoma model, Mel-gel-assisted HAIC demonstrated remarkable therapeutic efficacy, achieving a tumor inhibition rate of 98.09%, activating anti-tumor immune responses, and curing 60% of treated rats. This novel ultrasound-responsive hydrogel represents a promising advancement in hepatoma treatment, offering enhanced precision, efficacy, and safety. Additionally, Mel-gel’s versatile drug delivery capabilities may enhance the pharmacokinetics of various drugs and support synergistic therapies. This novel hydrogel system offers a promising advancement in hepatoma treatment, aiming to optimize outcomes and expand its application to other therapeutic agents.

Hemoperfusion has emerged as a crucial treatment for liver failure in clinics. However, the challenge remains in the incapacity to effectively and concurrently eliminate multiple harmful toxins, including inflammatory cytokines and bilirubin. This study employed molecular docking for directing the design of adsorbents. To develop a multi-target adsorbent material for liver failure, capable of absorbing both bilirubin and tumor necrosis factor-α (TNF-α), a functional platform was constructed. This platform employs a TiO2-modified polystyrene-based microsphere PSVT, which was designed for bilirubin adsorption, and coated with polydopamine and grafted with epigallocatechin gallate (EGCG) for TNF-α adsorption. The results confirm that EGCG possesses a high binding affinity for TNF-α, and the introduction of EGCG as a functional moiety markedly improves the clearance effectiveness of TNF-α. Meanwhile, PSVT served as the foundation to guarantee the effective removal of bilirubin. PSVT/P/EGCG exhibits outstanding clearance performance, with a maximum adsorption capacity of 263 ng/g for TNF-α and 23.91 mg/g for bilirubin, demonstrating its high efficiency in removing both inflammatory mediators and toxins. EGCG contributes exceptional antioxidant capabilities to PSVT/P/EGCG. The adsorbent exhibits remarkable biocompatibility and stability. The multi-target adsorbent material developed in this study has an extensive spectrum of potential applications in liver failure treatment employing an artificial liver.

This study reports an electrocatalytic cathode material (Co3O4/ZnO@RGO) constructed by integrating a bimetallic oxide heterojunction (Co3O4/ZnO) with a porous conductive reduced graphene oxide aerogel for lithium-sulfur batteries. This design aims to enhance the performance of lithium-sulfur batteries through interfacial catalysis and accelerated electron transport. The three-dimensional porous graphene aerogel network provides stable support for charge carriers while constructing rapid electron transport pathways for sulfide species, effectively mitigating volume expansion and accelerating charge migration. Meanwhile, the Co3O4/ZnO heterostructure serves as an adsorption and catalytic center for lithium polysulfides, accelerating the redox reaction kinetics of sulfur species while suppressing the shuttle effect. The Co3O4/ZnO@RGO electrode delivered an initial discharge capacity of 1590 mAh g-1 at 0.1C and maintained a reversible capacity of 1079 mAh g-1 after 250 cycles. At an E/S ratio of 7.5 μL mg-1 and 1C, the cathode exhibited a low capacity decay rate of 0.15% per cycle over 400 cycles. In addition, at a sulfur loading of 3 mg cm-2 and 5C, it still delivered a reversible capacity of 320 mAh g-1, demonstrating the robustness of the heterostructure/aerogel design and its promise for the development of advanced lithium-sulfur batteries.

We report a high-level theoretical investigation of the four-dimensional intermolecular potential energy surface (PES) and rovibrational bound states of the HF–N2O complex. The PESs were constructed at the CCSD(T)-F12a level using aug-cc-pVXZ (X = T, Q) basis sets, and extrapolated to the complete basis set (CBS) limit. The resulting surface exhibits a complex topology with two hydrogen-bonded minima and five saddle points that govern interconversion between the bent and linear isomers. The global minimum corresponds to the planar bent NNO···HF structure, while the linear ONN···HF configuration is a nearly isoenergetic local minimum. In terms of dissociation energy (D0), the bent isomer is only 1.85 cm−1 more stable than that of the linear one. The low-lying intermolecular vibrational states of both isomers were subsequently assigned by analyzing the nodal surfaces of the wavefunctions. The calculated results were then directly compared with those of high-resolution microwave measurements. Excellent agreement was achieved for the linear isomer, with an RMS error of 0.0014 cm−1 for the four observed transitions. For the bent isomer, the overall RMS deviation for the 14 transitions is 0.0202 cm−1 with most spectroscopic constants in good agreement, except for a notably larger discrepancy in A + DK. We trace this discrepancy to the large-amplitude vibrational averaging and the particular sensitivity of the a-axis moment of inertia to the intermolecular bending coordinate. Overall, these results establish a direct connection between high-level ab initio potentials and the observed rovibrational structure in floppy hydrogen-bonded complexes.

Current αβT cell-based immunotherapies largely relying on the use of autologous T cells not only face limitations such as complex manufacturing processes, long production cycles, and high costs, but are also susceptible to immune escape due to tumor antigen loss or downregulation. In contrast, γδT cells offer a unique "off-the-shelf" advantage owing to their HLA-independent recognition of tumor cells, enabling them to target and eliminate malignancies through multiple mechanisms without the need for patient-specific matching. To address the suppressive tumor microenvironment that often impedes γδT cell functions, this study developed an injectable hydrogel system based on oxidized dextran-gelatin for the localized co-delivery of γδT cells along with activating stimulants-IL-2 and zoledronate. This hydrogel with tunable gelation behavior and excellent biocompatibility facilitates sustained release of its cargo. In this system, IL-2 serves as an essential cytokine for supporting the survival, expansion, and functional maintenance of γδT cells, while zoledronate further promotes the proliferation and activation of γδT cells, thereby enhancing their antitumor immune response. In a subcutaneous human osteosarcoma xenograft model, local delivery of CAR-γδT cells combined with zoledronate and IL-2 via this hydrogel system significantly suppressed tumor progression and extended survival. This study thus presents an immunomodulatory strategy to potentiate γδT cell-based therapy against solid tumors.