Homotypic targeted nanoplatform enable efficient chemoimmunotherapy and reduced DOX cardiotoxicity in chemoresistant cancer via TGF-β1 blockade.

Doxorubicin (DOX) with broad-spectrum antitumor activity has been reported to induce effective immunogenic cell death (ICD) effect. However, the serious cardiotoxicity and chemoresistance severely restrict the widely clinical application of DOX. Herein, for the first time, a bio-inspired nanoplatform via co-assembly of DOX-conjugated polyethyleneimine (PEI-DOX), cancer cell membrane (CCM) and TGF-β1 siRNA (siTGF-β1) was rationally designed, which can not only overcome the drawbacks of DOX but also display high capability to modulate the tumor microenvironment and prevent the tumor progressing and metastasis. Experimental studies confirmed the pH-sensitivity of PEI-DOX and the homotypic-targeting and immuno-escapable ability of CCM, resulting an enhanced accumulation of DOX and siTGF-β1 in tumor sites. In addition to this, the bio-inspired nanoplatform could also improve the stability and facilitate the endosomal escape of siTGF-β1. All these effects ensured the silence efficiency of siTGF-β1 in tumor sites, which could further modulate the chemoresistant and immunosuppressive tumor microenvironment, resulting a synergistic effect with DOX to prevent tumor progressing and metastasis. Additionally, even trapped in cardiac tissues, siTGF-β1 could inhibit the production of TGF-β1 and ROS induced by DOX, resulting a reduced myocardial damage. Therefore, our newly designed bio-inspired nano-delivery system may be a promising nanoplatform with efficient chemoimmunotherapy to ameliorate DOX-induced cardiotoxicity and combat tumor growth and metastasis in chemoresistant cancer.