Bio-Photo Dual Action of Intracellular Radical Polymerization

Achieving spatiotemporal control over intracellular polymerization presents a fundamental challenge in merging synthetic chemistry with living systems. Here, we introduce a stimuli-responsive photocatalyst strategy that enables biomarker- and light-gated radical polymerization within cells. Engineered 3,4,5,6-tetrabromofluorescein (TBF) photocatalysts incorporate protecting groups─responsive to endogenous reactive oxygen/sulfur species (ROS/RSS) or enzymes─that suppress photoinduced electron/energy transfer-reversible addition-fragmentation chain transfer (PET-RAFT) activity until simultaneous biomarker activation and irradiation occur. This AND-gated mechanism confines polymerization exclusively to target cells. Leveraging monomer design and this dual-control paradigm, in situ polymer growth selectively disrupts endoplasmic reticulum (ER) integrity, triggering ER stress, calcium release, and paraptosis─a caspase-independent cell death pathway characterized by cytoplasmic vacuolization and ER dilation. This platform establishes a versatile chemical approach for precision organelle intervention, advancing therapeutic discovery and synthetic biology applications.