pH-Responsive Resveratrol Liposomes Targeting Sigma1 Receptor Attenuate Renal Fibrosis by Remodeling the Renal Microenvironment

Renal fibrosis (RF), a critical pathogenic mechanism in chronic kidney disease (CKD), now has exceedingly few therapeutic alternatives. This study presents a new sigma1 receptor (σ1R)-targeted nanodelivery system utilizing the natural polyphenolic medicine resveratrol (Res) as a therapeutic agent, addressing its low bioavailability and inadequate targeting properties, thereby providing a significant advancement in the treatment of RF. We engineered and produced a multifunctional material, aminoethyl anisamide-poly(2-ethyl-2-oxazoline)-cholesterol hemisuccinate (APC)-with benefits including active targeting, prolonged circulation, and pH sensitivity. <i>In vitro</i> investigations demonstrated that in the high glucose-induced HK-2 cell fibrosis model, the absorption efficiency of APC-modified liposomes was markedly enhanced, effectively suppressing the expression of fibrotic and inflammatory factors. In two typical animal models of RF, namely diabetic nephropathy and glomerulonephritis, APC@Res demonstrated therapeutic advantages, including modulation of the TGF-β1/Smad3 signaling pathway to impede fibrosis, a notable reduction in oxidative stress levels, enhanced renal function parameters, and diminished expression of inflammatory and fibrotic markers. This study innovatively employs the renal microacidic environment and sigma1 targeting to develop an effective delivery system, offering a novel treatment strategy for reversing RF.