Sigma1 Receptor-Targeted pH-Responsive Nanoemulsions Delivering Tanshinone IIA to a Reverse Renal Fibrotic Microenvironment

Renal fibrosis (RF) is a primary pathogenic process that propels the advancement of chronic kidney disease (CKD) to end-stage renal failure. Irrespective of the origin of CKD, both renal tubulo-interstitial tissue and glomeruli experience fibrotic alterations. In this study, two functionalized amphiphilic polymers based on the specific ligand of the sigma1 receptor (σ1Rs)-aminoethyl anisidine (AEAA) were innovatively developed: pH-responsive AEAA-poly(2-ethyl-2-oxazoline)-cholesteryl methyl carbonate (AEAA-PEtOz-CHMC, APC) and long-circulation AEAA-polyethylene glycol-1,2-distearoyl-sn-glycerol-3-phosphoethanolamine (AEAA-PEG-DSPE, APD) for renal-targeted delivery of tanshinone IIA (Tan IIA). The therapeutic efficacy of different Tan IIA nanoemulsions (Tan IIA-NEs) was systematically evaluated in two established RF models: the unilateral ureteral obstruction model, which simulates renal interstitial fibrosis, and the doxorubicin hydrochloride-triggered glomerulonephritis model, which mimics human focal segmental glomerulosclerosis. In these RF models, compared to the model, Tan IIA-NE, and APD-Tan IIA-NE groups, the APC-Tan IIA-NE group demonstrated a marked improvement in kidney function, reduced oxidative damage, inhibited inflammation, mitigated fibrogenesis, and reversed the epithelial–mesenchymal transition. The pH-responsive drug release in acidic fibrotic environments together with σ1Rs-mediated cellular uptake facilitated effective therapeutic outcomes. This dual-targeting strategy reduced the degree of fibrosis by 36.83% in progressive RF models compared to conventional treatments. Our research demonstrates that microenvironment-responsive nanocarriers serve as a model for precision RF therapy by enabling spatial-temporal regulation of medication bioavailability.