Hyaluronic Acid-Modified N,N,N-trimethyl Chitosan-Poly (β-Aamino Ester) Nanocarriers Loaded with miR210 for Targeted Inhibition of Renal Fibrosis.

BACKGROUND: The clinical application of miR210, which possesses the capability to effectively alleviate renal interstitial fibrosis (RIF), is greatly constrained by its poor stability and lack of targeting abilities. METHODS: A hyaluronic acid-modified N,N,N-trimethyl chitosan-poly (β-amino ester) nanoparticle encapsulating miR210 (HTP@miR210) was constructed. The serum stability, microscopic morphology, particle size, and zeta potential were characterized through gel electrophoresis, transmission electron microscopy, and dynamic light scattering. Subsequently, the cellular uptake capacity and targeting ability of the NPs were evaluated through fluorescence imaging. Furthermore, the biosafety was assessed via CCK-8 experiment, hemolysis test, and comprehensive blood chemistry examinations. Additionally, a TGF-β1-induced RIF cell model was established, and the therapeutic potential of HTP@miR210 against RIF in vitro was evaluated through qRT-PCR, Transwell assays, tube formation experiments, and Western blot (WB). Finally, a unilateral ureteral obstruction (UUO) rat model was constructed, and the therapeutic activity of HTP@miR210 against RIF was further verified using qRT-PCR, H&E staining, Masson's trichrome staining, immunohistochemistry, Flow cytometry (FCM), and WB. RESULTS: HTP@miR210 exhibited a regular spherical shape. It demonstrated good stability in serum, as well as excellent biocompatibility and hemocompatibility. Additionally, it showed favorable renal targeting and promoted cell proliferation and angiogenesis. In animal experiments, HTP@miR210 effectively improved renal function and alleviated RIF. Specifically, it upregulated the expression of CD31 to promote angiogenesis and effectively inhibited the expression of α-SMA and fn1. CONCLUSIONS: This study underscored the tremendous potential of HTP@miR210 as an effective therapeutic approach for the treatment of RIF.