Photoresponsive Discoidal Polymersomes With Tracelessly Crosslinkable Bilayers for Intracellular Drug Delivery

Hierarchical biological structures inspire the design of synthetic nanomaterials, yet bottom‐up access to nonspherical polymersomes, particularly discoidal architectures like red blood cells (RBCs)—remains elusive due to thermodynamic constraints. Moreover, stimuli‐responsive control over such nonspherical vesicles is largely unexplored. Here we report photoresponsive block copolymer (BCP) amphiphiles bearing photolabile thiocoumarin units in the hydrophobic side chains that self‐assemble into five distinct nanostructures, including rare polymersome discocytes (PDs), by tuning block ratio and water addition rate during cosolvent‐mediated self‐assembly. Discocytes display superior cellular uptake compared to other morphologies. Visible light irradiation triggers thiocoumarin cleavage to generate primary amines that spontaneously undergo amidation, yielding in situ crosslinking that maintains the discocyte shape while simultaneously increasing bilayer membrane permeability. This dual action ensures morphological preservation during photo‐controlled selective release of hydrophilic cargos. These findings establish a general bottom‐up strategy for constructing biomimetic, shape‐engineered, and stimuli‐responsive vesicles, opening avenues for next‐generation therapeutic and diagnostic platforms.