Dual-targeting macrophage membrane nanosystem enhances radiotherapy-induced antitumor immunity via synergistic nuclear and mitochondrial DNA damage

Abstract

Radiotherapy (RT) can trigger immune-related signaling in addition to its direct cytotoxic effects. However, in many cases, this immune activation is not strong enough to produce durable antitumor immunity. One important reason is that RT-induced nuclear DNA damage mainly activates the DNA damage response (DDR), which in turn dampens inflammatory signaling and restricts further immune amplification. Previous studies have suggested that mitochondrial stress participates in innate immune regulation through the cytosolic accumulation of mitochondrial nucleic acids; nevertheless, effective approaches to enhance mitochondrial stress during RT, especially in brain tumors where delivery is limited, remain to be established. Here, we developed a macrophage membrane–encapsulated, KLA-modified gold nanoparticle system (MKA) to reinforce mitochondrial-associated stress under RT and improve tumor delivery efficiency. Guided by inflammation-associated homing and RT-induced local inflammatory priming, MKA exhibits enhanced accumulation in brain tumors with a compromised blood–brain barrier. After irradiation, MKA localizes to mitochondria, induces mitochondrial membrane depolarization and increased permeability, and promotes cytosolic accumulation of mitochondrial RNA together with activation of the RIG-I–MAVS pathway, leading to elevated type I interferon signaling. In line with these effects, combined MKA and RT treatment enhances intratumoral CD8⁺ T-cell infiltration and suppresses glioma growth. Collectively, these findings suggest that strengthening mitochondrial-associated stress, together with inflammation-guided delivery, can potentiate RT-induced innate immune signaling and improve radiotherapy-associated immune responses in brain tumors.