Degradable tumor-specific H2S nanogenerators for disrupting tumor metabolic symbiosis and activating anti-tumor immune responses.

[Display omitted] • Targeting degradation and releasing therapeutic components. • Targeting lactate metabolism, inducing multiple acidosis and reducing ATP production. • Dual pathway to improve chemodynamic therapy. • Reversing the tumor immunosuppressive microenvironment from multiple perspectives to enhance immunotherapy. The design of highly efficacious nanotherapeutic agents that target tumors and degrade in specific response is of great relevance and developmental promise. We have designed a tumor-specific decomposable H 2 S nanogenerator for the purpose of safely and effectively disrupting tumor metabolic symbiosis and activating anti-tumor immune responses. Dendritic mesoporous organosilica doped with Mn2+ (DMOM) was used as a H 2 S donor that could be specifically degraded in response to glutathione (GSH), and then α-Cyano-4-hydroxycinnamic acid (CHC, a monocarboxylate transporter protein inhibitor) was loaded on the pores and surface of the organosilica through a condensation reaction, and further modified with hyaluronic acid (HA). The H 2 S nanogenerator could target the tumor site and undergo continuous self-degradation, releasing doped Mn2+ and loaded CHC while depleting GSH and generating large amounts of H 2 S, which could ultimately destroy lactate metabolic symbiosis, induce multiple acidosis in tumor cells, reduce intracellular adenosine triphosphate (ATP) and enhance chemodynamic therapy. More importantly, both the H 2 S produced and the inhibition of lactate efflux could have an immunomodulatory effect and exert a positive influence on the activation of the immune system. Therefore, the tumor-specific degradable H 2 S nanogenerator with diverse therapeutic functions introduced in this work is expected to provide a new idea and a new paradigm for efficient anti-tumor therapy. [ABSTRACT FROM AUTHOR]