Hydroxyl-augmented gold nanorods via lactone ring-opening alleviate cisplatin nephrotoxicity through Nrf2 activation

Cisplatin-induced acute kidney injury (AKI) epitomizes a critical barrier and paradox in cancers, where dose-limiting nephrotoxicity propelled by oxidative cascades lacks targeted interventions. This pressing clinical dilemma underscores the paramount need for kidney injury mitigation, while existing therapeutic strategies fail to achieve it due to inadequate efficacy and specificity. Here, we introduce a lactone ring-opening chemistry approach to amplify hydroxyl-driven redox modulation on gold nanorods (Au-M NRs), addressing the unmet need for precision antioxidant delivery. Specifically, the sequential functionalization of gold nanorods with thiolated polyethylene glycol amine (HS-PEG₂₀₀₀-NH₂) and 5,8-dihydroxypsoralen (5,8-DHP) triggered a structural transformation, cleaving the six-membered lactone ring of 5,8-DHP and generating an additional phenolic hydroxyl group. In cisplatin-challenged HK-2 cells, hydroxyl-enriched Au-M markedly attenuated reactive oxygen species (ROS) level and activated Keap1/Nrf2 pathway, evidenced by upregulated SOD and antioxidant Nqo1 expression alongside suppressed MDA and prooxidant Nox2 levels. SiNrf2 transfection severely abrogated the cytoprotective effects of Au-M, while Nrf2 overexpression synergistically enhanced the anti-apoptotic efficacy of Au-M in renal tubular epithelial cells. Mirroring cellular outcomes, the Au-M nanosystem elicited potent renoprotection via Nrf2-orchestrated transcriptional reprogramming in vivo, concurrently preserving the integrity and safety of healthy tissues. Critically, Au-M NRs conferred sustained protection in chronic exposure models, exhibited biocompatibility upon repeated dosing, and accelerated renal recovery, affirming their long-term therapeutic viability. This lactone-to-phenol conversion strategy pioneers a topology-guided paradigm for redox homeostasis regulation beyond AKI, establishing a transformative platform to harness natural product derivatization in combating organ-specific oxidative injury.