Modulation of MOF Energy State to Construct Smart Activated Sensitizers for Membrane Directed C–H Ketene Therapy in Tumor Cells

Abstract

ABSTRACT Phospholipid oxidation closely links tumorigenesis to tumor microenvironment (TME) remodeling, easily producing lipid peroxides that cause inflammation and membrane damage. The inherent complexity and unpredictable biological effects of phospholipid peroxidation necessitate precision catalytic platforms for selective amplification of specific oxidized lipid species to enable mechanistic studies. We engineered a supramolecular smart composite material, SD‐1@PCN‐Ru, by integrating a ruthenium‐modified metal‐organic framework (MOF) with the receptor tyrosine kinase (RTKs)‐targeting fluorescent probe (SD‐1). This design leverages MOFs’ tunable porosity and catalytic versatility to spatially confine oxidative activity at tumor membranes via RTKs overexpression. Ru‐modified MOFs exhibit enhanced capabilities in photoinduced oxygen activation and electron transfer compared to their pristine counterparts, thereby facilitating phospholipid ketenization. Lipidomics reveals selective depletion of phosphatidylethanolamine (PE) and phosphatidylcholine (PC) at plasma membranes, compromising integrity while generating immunostimulatory oxidized lipids. Concurrently, the excessive reactive oxygen species (ROS) generated by SD‐1@PCN‐Ru activate caspase‐1/3 and GSDMD, thereby inducing immunogenic cell death and remodeling the immunosuppressive TME. In vitro/vivo studies demonstrate tumor‐specific cytotoxicity and growth suppression surpassing non‐targeted analogs, achieved through precision oxidative damage and immune activation. This work pioneers intelligent nanocomposites merging catalytic efficiency with molecular targeting, offering a transformative strategy for lipid peroxidation‐mediated TME modulation via synthetic‐biological integration.