Radiation‐Responsive Coacervates Through Controlled Self‐Immolative Demembranization

Abstract Coacervates formed through liquid–liquid phase separation (LLPS) have been utilized to emulate the dynamic organization of membraneless organelles in biological systems. These structures exhibit broad application prospects in biomedicine, especially as microreactors for biochemical reactions. However, membraneless coacervates tend to coalesce easily in ambient condition and lack the ability to achieve precise, stimulus‐responsive release, which presents significant challenges for their biomedical applications. To address this, we developed a self‐immolative polymer (SIP)‐membranized coacervates to tune enzyme cascade kinetics using radiotherapeutic γ‐ray. The SIP‐membranized coacervates exhibited enhanced kinetic stability and fusion‐resistance. When exposed to radiation, the SIP membrane undergoes depolymerization, resulting in increased fluidity and enhanced transmembrane transport. This, in turn, regulated enzyme cascade reactions within the coacervates. Specifically, we used radiation‐responsive coacervates to precisely modulate the generation of NO in living cells and exploited NO‐mediated radiosensitization to enhance cytotoxicity. Our findings advance the development of radiation‐responsive LLPS constructs, and pave the way for innovative applications in cellular bioengineering, and combined radio‐chemotherapy.