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

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.