Reversing the immunosuppressive tumor microenvironment by targeting metabolic competition between tumors and immune effector cells could induce tumor starvation and enhance the activity of immune cells, representing a potential approach to boost tumor immunotherapy. However, its actual efficacy is limited by compensatory oxidative phosphorylation (OXPHOS) energy replenishment and low delivery efficiency. Herein, we report a hydrogen sulfide (H2S)-self-supplying nanoplatform that orchestrates a dual blockade of glycolysis and OXPHOS for improved triple-negative breast cancer (TNBC) immunotherapy. The micellar system, HA-ADT@W, achieves tumor-targeted delivery of a glycolysis inhibitor (WZB117) and H2S continually released in GSH-overexpressed tumor cells. This strategy concurrently suppresses glucose uptake in tumor cells by reversing the acidic tumor microenvironment (TME) and disrupts compensatory OXPHOS via H2S-mediated inhibition of cytochrome c oxidase. Consequently, we demonstrate a significant rewiring of tumor energy metabolism that not only induces immunogenic cell death with remodeling of the immunosuppressive TME but also alleviates nutrient constraints of immune effector cells, leading to enhanced infiltration and function of cytotoxic immune cells. This work exhibits a smart nanoplatform-based H2S self-supplied micelle for reinforced TNBC immunotherapy via regulated metabolic competition between tumors and immune effector cells with TME normalization.
Siyu Meng, Xuan Wei, Ziyan Wang et al.· Advances in Materials· 0 citations
The introduction of reversible physical cross-linking constitutes a viable strategy for fabricating hydrogels with excellent mechanical properties, efficient self-recovery, and shape-memory capability. In this study, tannic acid-functionalized cellulose nanofibrils (TA@CNF) served as the core functional filler and were incorporated into a polyacrylamide-acrylic acid-stearyl methacrylate (P(AAm-AAc-SMA)) matrix to construct a nanocomposite hydrogel. In this system, TA@CNF not only served as a nanoscale reinforcing phase but also synergistically participated in the construction of multiple physical cross-linking networks through its abundant phenolic hydroxyl functional groups on the surface. Specifically, the polymeric network was stabilized by the incorporation of four distinct physical reinforcement mechanisms. These include (i) nanoparticle reinforcement provided by TA@CNF; (ii) hydrophobic associations among the PSMA segments; (iii) hydrogen bonding, which occurs both between TA@CNF and PSMA and within each individual component; and (iv) multiple metal-coordination bonds formed between Fe3+ ions and the phenolic groups of TA@CNF, as well as the carboxyl groups of PAAc segments. Benefiting from the pivotal bridging role of TA@CNF across the aforementioned multiple physical cross-linking networks, the resulting TA@CNF/P(AAm-AAc-SMA)/Fe3+ hydrogels (THFs) exhibited significantly improved mechanical properties. The optimal hydrogels demonstrated excellent mechanical performance, with a high tensile strength (8.31 MPa), elongation at break (700%), and toughness (39.59 MJ·m–3). Owing to reversible physical cross-links and TA@CNF flexibility, the hydrogels also showed self-recovery (achieving 52% toughness recovery within 10 min), outstanding fatigue resistance, and reliable shape-memory performance. The mechanical properties and multifunctional performance of these tough hydrogels made them well-suited for use in load-bearing and soft actuator applications.