A Microenvironment-Adaptive Nanoadjuvant Resolves the Radioprotection and Radiosensitization Paradox in Cancer Therapy

Abstract The intrinsic spatiotemporal discord between augmenting tumor radiosensitivity and safeguarding normal tissue has persistently circumscribed the therapeutic horizon of radiotherapy. Here, we introduce a microenvironment-adaptive platform, cross-linked lipoic acid nanoadjuvant (cLAN), designed to strategically navigate this dilemma. Upon cellular internalization, cLAN dissociates into the lipoic acid (LA)/dihydrolipoic acid (DHLA) redox pair, which elicits distinct biological responses in normal vs tumor cells. In irradiated normal cells, the LA/DHLA system primarily scavenges radiation-induced reactive oxygen species (ROS), thereby conferring radioprotection. In tumor cells, the relatively high reducing environment shifts the LA/DHLA equilibrium toward the reduced DHLA state, which further promotes Fenton reactions and aggravates oxidative stress. Together with the suppression of NF-κB-mediated DNA damage repair, these effects ultimately potentiate tumor radiosensitivity. Under total body irradiation, cLAN efficiently mitigates radiation-induced damage, particularly preserving marrow DNA content and maintaining nucleated cell counts at normal levels, far surpassing clinical standard radioprotector amifostine. Meanwhile, cLAN elicits tumor radiosensitization comparable to clinical standard radiosensitizer sodium glycididazole. Such compatibility of efficacy-safety achieves 100% 30-day survival in both subcutaneous and orthotopic mouse tumor models. This study demonstrates the potential of this microenvironment-adaptive strategy for radiotherapy by simultaneously achieving radioprotection and radiosensitization within the same spatiotemporal domain.