Ultrasound-triggered cascade-targeted nanoplatform enables controllable precision delivery for enhanced acute kidney injury therapy

Acute kidney injury (AKI) suffers from limited therapeutic efficacy largely owing to insufficient targeted accumulation and uncontrollable on-demand delivery of conventional therapeutics. To overcome these drug delivery bottlenecks, we develop an ultrasound-triggered cascade-targeted nanoplatform (LSMND). Different from conventional static nanocarriers with fixed particle sizes, LSMND achieves controllable in situ particle remodeling and deep renal delivery through ultrasound-activated perfluoropentane (PFP) liquid-gas phase transition. Surface-functionalized LTH peptides further endow LSMND with active targeting ability, enabling precise enrichment in injured proximal tubules. The oxidative microenvironment induces the cleavage of ROS-responsive thioketal (TK) linkages, triggering programmed disassembly of LSMND and spatiotemporal co-delivery of SS31 and MCC950. The released SS31 preserves mitochondrial structural integrity and ameliorates mitochondrial bioenergetics, thereby restricting mtDNA leakage and suppressing Z-DNA binding protein 1 ( Zbp1 )-associated inflammatory activation. MCC950 suppresses the NLRP3 inflammatory cascade, synergistically potentially alleviates the detrimental metabolic-inflammatory loop. Integrated proteotranscriptomic analyses verify that LSMND alleviates upstream mitochondrial stress and blocks aberrant pro-inflammatory activation. In a murine renal ischemia-reperfusion injury model, LSMND substantially alleviates tubular necrosis and promotes renal functional recovery. This US-activated cascade-targeted nanoplatform provides a controllable and precise therapeutic strategy for AKI treatment.