Generation of GPC-3-targeted radicals for precise therapy of hepatocellular carcinoma.

Exogenous free radicals oxidize and damage tumor proteins, but their non-specific reactivity also causes unintended harm to tumor-suppressive proteins, which compromises the therapeutic efficacy. Here we show a nanosystem that generates in-situ radical-conjugated species with predefined targeting capability toward oncogenic protein. This nanosystem consists of lipid nanoparticles encapsulating polyphenolic tannic acid and hydrophobic calcium peroxide nanoparticles in spatially segregated compartments. Upon cellular uptake, the components are released into the cellular membrane through membrane fusion. Consequently, calcium peroxide nanoparticles act as oxidizing agents, radicalizing tannic acid, which generates gallic acid species conjugated with phenoxyl radicals. Since gallic acid confers specific binding affinity for the oncogenic GPC-3 protein in hepatocellular carcinoma, the radical-conjugated species integrate dual functionalities: a targeting module that binds to the oncogenic GPC-3 protein, and a stabilized phenoxyl radical inducing site-specific oxidative damage. These species direct to GPC-3 and induce localized disruption of critical peptide segments and lipid domains, triggering protein cleavage and membrane shedding, which suppresses downstream signaling including the canonical Wnt/β-catenin pathway and finally inhibits hepatocellular carcinoma progression. By enabling site-specific radical delivery, this strategy achieves precise inactivation of predefined oncogenic targets and establishes a framework for molecularly free-radical-mediated antitumor therapy.