Bioinspired platelet membrane-cloaked ROS-responsive nanozymes enable synergistic therapy of acute kidney injury via immunomodulation and ferroptosis suppression.

Abstract

Acute kidney injury (AKI) is a prevalent clinical syndrome associated with high morbidity, mortality, and a heavy medical burden. Oxidative stress, inflammation, and ferroptosis are key drivers of AKI, yet current pharmacotherapies are limited by suboptimal efficacy and systemic side effects. An efficient and precise kidney-targeted delivery system that co-delivers complementary therapeutics could overcome these challenges. Herein, we report a platelet membrane-coated, reactive oxygen species (ROS)-responsive nanozyme (BAPCs@PM) for synergistic AKI therapy. Ultrasmall CeO2 nanodots (~3 nm) were in situ mineralized on the outer layer of polydopamine cores, and hydrophobic baicalein was loaded into the mesoporous interior, yielding a stable and well-dispersed multifunctional composite nanozyme. Platelet membrane cloaking conferred renal targeting, immune evasion, and prolonged circulation. BAPCs@PM enabled ROS-triggered release of CeO2 nanodots and sustained baicalein delivery at injured sites, amplifying local antioxidant, anti-inflammatory, and anti-ferroptotic activity. In a cisplatin-induced AKI model, BAPCs@PM markedly suppressed kidney injury molecule-1 upregulation, inhibited cleaved caspase-3 activation and apoptosis, enhanced mitochondrial protection, modulated macrophage polarization, reduced proinflammatory cytokine production, regulated iron homeostasis, restored glutathione peroxidase 4 expression, attenuated ferroptosis and lipid peroxidation, and ultimately improved renal function. Owing to their ultrasmall size, the ceria nanodots achieved efficient renal accumulation and rapid clearance with minimal systemic toxicity. This study provides an innovative biomimetic and responsive therapeutic strategy for AKI by combining ultrasmall nanozymes, natural bioactive molecules, and biomimetic membrane engineering.