报道了广谱抗肿瘤活性的阿霉素（DOX）能够引起有效的免疫细胞死亡（ICD）效应。然而，严重的心脏毒性和化疗抵抗严重限制了DOX的广泛临床应用。在这里，我们首次设计了一种生物启发的纳米平台，通过DOX共轭聚乙烯亚胺（PEI-DOX）、癌细胞膜（CCM）和TGF-β1 siRNA（siTGF-β1）的共组装，既能克服DOX的缺点，又能高效调控肿瘤微环境，防止肿瘤进展和转移。实验研究证实了PEI-DOX的pH敏感性以及CCM的同源靶向和免疫逃避能力，从而增强了DOX和siTGF-β1在肿瘤部位的积累。此外，生物启发的纳米平台还能改善siTGF-β1的稳定性并促进其逃脱内质网。所有这些效应确保了siTGF-β1在肿瘤部位的有效沉默，进一步调节化疗耐药和免疫抑制的肿瘤微环境，与DOX产生协同效应以防止肿瘤进展和转移。此外，即使被困在心脏组织中，siTGF-β1也能抑制DOX诱导的TGF-β1和ROS的产生，从而减轻心肌损伤。因此，我们设计的这种新型生物启发的纳米递送系统可能是一种具有有效的化疗免疫疗法的有前途的纳米平台，用于改善DOX诱导的心脏毒性和对抗化疗耐药癌症的肿瘤生长和转移。版权所有 © 2023 Elsevier B.V.发表。

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.Copyright © 2023. Published by Elsevier B.V.