Radiation-Responsive Coacervates through Controlled Self-Immolative Demembranization

Abstract: In biology systems, membrane dynamics are integral to regulating biological pathways by mediating signaling communication between membraneless and membranized microcompartments. Notably, biomimetic constructs emulating these dynamics have emerged as powerful tools to provide insights into complex biological processes. Among these, the controlled demembranation of membranized coacervates represents a promising approach to endow them with additional functionalities and capabilities in response to external biological stimuli. Here, we developed a self-immolative polymer (SIP)-membranized coacervate capable of undergoing controlled demembranization upon exposure to γ-ray. Membranization endows coacervates with high stability and remarkable salt resistance. Significantly, SIP-membranized coacervates demonstrate spatial organization whereby various enzymes can be located in discrete regions, which facilitates an on/off modulation for a cascade enzymatic reaction. When exposed to γ-ray, SIP membrane undergoes controlled depolymerization, the fusion of these discrete spatial organization enhanced enzymatic cascade kinetics within the coacervates. Specifically, SIP-membranized coacervates carrying enzymes are incorporated as active artificial organelles in living cells and regulate enzymatic cascade reactions that generate nitric oxide (NO). Nitric oxide served as a radiosensitizer, further reducing cell viability. Our findings advance the development of radiation-responsive LLPS constructs and pave the way for innovative applications in cellular bioengineering and combined radio-chemotherapy.