Ruthenium(II) Lipid‐Mimics Drive Lipid Phase Separation to Arouse Autophagy‐Ferroptosis Cascade for Photoimmunotherapy

Abstract Lipid‐mediated phase separation is crucial for the formation of lipophilic spontaneous domain to regulate lipid metabolism and homeostasis, furtherly contributing to multiple cell death pathways. Herein, a series of Ru(II) lipid‐mimics based on short chains or midchain lipids are developed. Among them, Ru‐LipM with two dodecyl chains significantly induces natural lipid phase separation via hydrocarbon chain‐melting phase transitions. Accompanied by the aggregation of Ru‐LipM ‐labeled lipophilic membrane‐less compartments, most polyunsaturated lipids are increased and the autophagic flux is retarded with the adaptor protein sequestosome 1 (p62). Upon low‐dose irradiation, Ru‐LipM further drives ferritinophagy, providing an additional source of labile iron and rendering cells more sensitive to ferroptosis. Meanwhile, the peroxidation of polyunsaturated lipids occurs due to the deactivation of glutathione peroxidase 4 (GPX4) and the overexpression of acyl‐CoA synthetase long‐chain family member 4 (ACSL4), leading to the immunogenic ferroptosis. Ultimately, both innate and adaptive immunity are invigorated, indicating the tremendous antitumor capability of Ru‐LipM in vivo. This study presents an unprecedented discovery of small molecules capable of inducing and monitoring lipid phase separation, thereby eliciting robust immune responses in living cells. It provides a biosimulation strategy for constructing efficient metal‐based immune activators.