Shuang Jin, Daqing Xia, Lin Li, Huan He, Lei Liu, Yunyun Wu, Ting Zheng, Hongrui Zhu, Hanyin Zhu, Jixi Zhang
Proteins are central regulators of cellular function, and deliberate disruption of intracellular protein homeostasis represents a promising avenue for cancer immunotherapy. Despite its efficiency, aldehyde-mediated protein carbonylation faces major hurdles in localized tumor targeting without systemic toxicity for immunotherapy. This study proposed a therapeutic paradigm termed catalytic immunogenic modification, enabled by a plasmonically powered nanozyme system that programs protein modification in situ. Clustered palladium nanozymes with anchored linoleic acid (LA) substrates enable spatiotemporally confined generation of lipid peroxidation (LPO), derived aldehyde 4-hydroxynonenal (HNE) within tumor tissues. Benefiting from intrinsic peroxidase and catalase-like activities, the system converts tumor derived hydrogen peroxide into interfacial hydroxyl radicals and molecular oxygen to initiate localized LPO cascades, while pulsed laser driven plasmonic hot electron transfer further amplifies aldehyde production. High concentrations of aldehydes were generated in cells via this proximal catalytic process, among which the level of HNE produced by LA-loaded nanozymes was 3.8 times that produced by unloaded counterparts. The high concentration of aldehydes disrupted protein homeostasis and induced persistent endoplasmic reticulum (ER) stress, which triggered extensive externalization of calreticulin (CRT) to facilitate the phagocytosis of dying cells by dendritic cells (DCs) and further activated T cells to exert potent immune effects. The exposure rate of CRT on the surface of cells was 86.1%, and the phagocytosis rate of tumor cells by DCs reached 4.3 times that of the control group. By hijacking ER stress-mediated surveillance, this strategy converted confined catalytic energy into potent, programmable immunogenic signals, establishing a distinct approach for tumor immunotherapy.