A self-assembling manganese-peptide hydrogel bridges metabolic modulation and STING pathway activation for cancer...

The efficacy of cancer immunotherapy is frequently limited by immunosuppressive tumor microenvironments and a lack of advanced delivery systems capable of spatiotemporal immunomodulation. Herein, we report the rational design of a stimuli-responsive, self-assembling peptide hydrogel (Nap-ss-FFYK, N-ss-F) engineered to co-deliver manganese ions (Mn^2 +) while acting as an intrinsic metabolic modulator. The supramolecular N-ss-F@Mn hydrogel features a structural disulfide bridge that undergoes rapid cleavage upon exposure to the glutathione (GSH)-rich tumor microenvironment. This stimuli-responsive disassembly serves a dual therapeutic function: it facilitates the sustained release of Mn²⁺ to potently activate the cGAS-STING pathway, and it actively disrupts tumor redox homeostasis. The chemical reduction of the hydrogel depletes intracellular GSH, downregulating glutathione peroxidase 4 (GPX4) to induce ferroptosis. Concurrently, the compensatory GSH regeneration response heavily consumes intracellular NADPH, triggering actin cytoskeleton collapse and inducing disulfidptosis. By seamlessly integrating a biomimetic peptide scaffold with targeted metabolic disruption and STING-mediated immune priming, the N-ss-F@Mn hydrogel effectively reverses the "cold" tumor microenvironment. This multifunctional biomaterial platform demonstrates robust efficacy in inhibiting tumor growth and metastasis, highlighting the potential of metabolically active supramolecular assemblies in advancing cancer immunotherapy.