In situ self-assembled cell reservoir hydrogel for maneuvering multistage radioimmunotherapy

Radiotherapy (RT) is a clinical mainstay of cancer treatment that triggers tumor-specific immune responses. However, the effectiveness is usually hampered due to the hypoxic tumor microenvironment (TME) and the ambivalent impact of RT on the immune landscape of tumors. Herein, we develop an injectable hydrogel encapsulating interleukin-12 (IL-12)/anti-CTLA-4 (aCTLA-4) co-engineered red blood cells (RBC), which is in situ self-assembled within the TME to increase oxygen supply and instigate sequential aCTLA-4/IL-12 release, thus achieving Ba/O₂ self-compensated radiosensitization and activating multistage immune responses. Once in the acidic TME, the in situ injected BaO₂ undergoes hydrolysis to generate H₂O₂ and Ba²⁺, followed by the rapid reaction of Ba²⁺ with sodium alginate to afford a biocompatible hydrogel. Meanwhile, catalase presented on RBC converts H₂O₂ into O₂, thereby alleviating hypoxia-induced radioresistance and inducing O₂-mediated pore formation on RBC membrane for rapid release of aCTLA-4 to relieve tumor immunosuppression. Subsequently, IL-12 anchored on RBC is dilatorily released and interacts with T/NK cells within the TME to induce IFN-γ-dependent antitumor immunity. Taken together, the in situ self-assembled cell reservoir hydrogel offers a futuristic avenue to realize multistage radioimmunotherapy for effective tumor regression by programmable immunoregulation with significant clinical value.