Natural polyphenols alleviate multi-organ damage via mediating renal-muscle crosstalk and inhibiting the NLRP3/Caspase-1/GSDMD pyroptosis pathway

As a cornerstone chemotherapeutic for solid tumors, cisplatin (CDDP) faces clinical limitations due to dose-limiting toxicity, causing acute kidney injury (AKI) and muscle atrophy. CDDP-induced ROS activate the NLRP3/Caspase-1/GSDMD pyroptosis pathway in renal cells, triggering pyroptosis. Released IL-1β recruits immune cells, forming a “pyroptosis-inflammation-immune damage” cycle, while the ubiquitin-proteasome system (UPS) accelerates muscle loss. Current studies lack systematic analysis of pyroptosis’ spatiotemporal regulation in cross-organ injury and its interplay with oxidative stress and immune dysregulation. Herein, this study integrates natural proanthocyanidins with abundant catechol skeletons, manganese ions and human serum albumin (HSA) to fabricate ANT@Mn nanoparticles (ANT@Mn NPs) via metal coordination between phenolic hydroxyl groups of proanthocyanidins and Mn²⁺, with HSA assisting the assembly process. This nanoplatform achieves triple therapeutic effects that: (i) inhibits pyroptosis via ROS scavenging and NLRP3 blockade; (ii) regulates immunity by reducing IL-1β/IL-17 and modulating NK/T-cell activity; (iii) restores muscle protein homeostasis by suppressing UPS and activating mTOR. RNA-seq confirmed attenuated oxidative stress and inflammation. Experiments demonstrated simultaneous alleviation of kidney injury and muscle atrophy, offering a clinical strategy for CDDP toxicity and a “multi-target synergistic” nanomedicine paradigm.