A Radiotherapy‐Responsive Peptide Hydrogel for Pulsatile Release of mRNA‐LNPs Synergizes with Immune Activation to Prevent Breast Cancer Recurrence

Abstract

Abstract Adjuvant radiotherapy (ART) is a widely used treatment after tumor resection to prevent tumor recurrence. A major limitation of ART is the insufficient capacity to elicit durable antitumor immunity, typically due to inadequate tumor‐associated antigen supply. Although mRNA vaccines provide a promising strategy to supplement neoantigens, current delivery systems require multiple injections and lack spatiotemporal synchronization with radiotherapy. Here, a radiotherapy‐responsive peptide hydrogel (NBS Gel ) is first presented that enables radiation‐synchronized pulsatile release of mRNA‐loaded lipid nanoparticles (mLNPs). NBS Gel is formed by co‐assembling two sulfide‐modified peptides (NapS and BenS) with distinct oxidation sensitivities, yielding stepwise hydrogel disassembly under fractionated radiation. NBS Gel @mLNP enables pulsatile mLNP release from a single dose, mimicking multi‐injection vaccination while synchronizing antigen availability with DC recruitment. In tumor postoperative models, NBS Gel @mLNP combined with ART markedly amplifies antigen‐specific CD8⁺ T‐cell responses, reduces tumor relapse by 80%, and prolongs survival, outperforming intramuscular vaccination and non‐pulsatile controls. Tumor rechallenge experiment shows no tumor regrowth in the long‐term surviving mice, confirming a durable anti‐tumor immune memory. This work establishes a materials‐guided paradigm that achieves spatiotemporal synergy between radiotherapy and mRNA‐based immunotherapy through pulsatile antigen delivery, providing a clinically viable strategy for preventing postoperative cancer recurrence.