Inhibition of HSC proliferation and hepatic fibrogenesis with Erythrocyte membrane coated Doxorubicin/Black phosphorus nanosheets

Rapid proliferation underlies the abnormal expansion of activated hepatic stellate cells (aHSCs) and thereby contributes to the development and progression of liver fibrosis, so inhibition of HSC proliferation serves as a good antifibrotic strategy. As a potent topoisomerase II inhibitor, doxorubicin (DOX), an antineoplastic drug, exhibits a significant antifibrotic activity in vitro via retarding the growth of aHSCs and reversing their myofibroblastic phenotype, but its severe hepatotoxicity, cardiotoxicity, and renal toxicity limit its wide clinical application. Therefore, enhancing the specificity and efficacy of DOX in targeting aHSCs to improve its therapeutic index and minimize its adverse effects has become a key point for the success of DOX in antifibrotic treatment. In this study aimed at liver fibrosis treatment, we combined the excellent drug-loading capability and good biocompatibility of black phosphorus nanosheets (BPNSs), the protective and camouflaging properties of red blood cell membrane encapsulation, and the HSCs-targetability provided by the surface modification with vitamin A derivatives, into the construction of HSCs-targeted BP/DOX nanovesicles (BP/DOX@RMV-VA). The obtained DOX nanovesicles exhibited a uniform particle size and spheroid morphology, excellent diffusion property and stability, and high DOX loading. Specifically, they demonstrated outstanding biosafety, effective HSCs-targetability both in vivo and in vitro, and markedly improved pharmacokinetic profile of DOX. BP/DOX@RMV-VA produced strong antiproliferative and MF-phenotype reverting activity both in cultured aHSCs and in mice chronically injured by CCl 4 . And accordingly, the administration of BP/DOX@RMV-VA to CCl 4 -injured mice effectively suppressed the expansion of aHSCs and fibrogenesis, and significantly improved liver structure and function without causing detectable cardiotoxicity. These results highly suggest the therapeutic potential of BP/DOX@RMV-VA in treating liver fibrosis and other fibrosis-associated liver diseases.