Natural Killer Cell Membrane-Cloaked Virus-Mimicking Nanogenerator with NIR-Triggered Shape Reversal and •C/•OH Storm for Synergistic Thermodynamic–Chemodynamic Therapy

Free radical-based anticancer modality has been widely applied to cancer therapies. However, it still faces challenges of low delivery efficiency and poor selectivity of free radical generation specifically toward tumors. Herein, a virus-mimicking hollow mesoporous disulfide-bridged organosilica is designed to encapsulate •C precursor 2, 2'-azobis[2-(2-imidazolin-2-yl) propane] dihydrochloride (AIPH), which is then enclosed by tannic acid (TA)/FeIII photothermal assembly and further cloaked by natural killer (NK) cell membrane to achieve synergistic thermodynamic–chemodynamic therapy. The nanogenerator can first evade immune surveillance via NK cell membrane “cloaking” mechanism to strongly accumulate in tumors. Interestingly, the NIR laser-induced heat can trigger NK cell membrane rupture for “shape reversal” to expose a virus-like surface to amplify the cellular uptake, and simultaneously break the azo bonds of AIPH for in situ controlled •C generation. Then upon glutathione (GSH) triggering, the nanogenerator disintegrates via disulfide–thiol exchange and efficiently generates •OH by lysosomal pH-initiated TA-FeIII reaction; notably, the consumption of GSH can amplify oxidative stress to enhance free radical therapy by weakening the self-defense mechanism of tumor cells. It is envisioned that the NK cell membrane-cloaked virus-mimicking and NIR/GSH sequentially activated •C/•OH radical nanogenerator can provide a promising strategy for oxidative stress-based anticancer therapy.