肝细胞癌（HCC）是最常见的原发性肝癌类型，也是全球癌症相关死亡的第三大原因。由于其固有的对化疗的抵抗力，该肿瘤很难治疗。抗基质疗法是一种新颖的治疗方法，针对肿瘤微环境中的癌症相关成纤维细胞（CAF）。 CAF 衍生的微纤维相关蛋白 5 (MFAP-5) 被确定为具有高度翻译相关性的 HCC 抗基质治疗的新靶点。生物相容性的基于聚肽（O）化物的聚离子复合物胶束（PICM）由三嵌段共聚物构成，该三嵌段共聚物由阳离子聚（L-赖氨酸）通过静电相互作用络合抗 MFAP-5 siRNA（siMFAP-5），聚（γ-）苄基-L-谷氨酸）通过 π-π 相互作用阻断负载阳离子两亲性药物地氯雷他汀 (DES) 作为内体逃逸增强剂，并通过聚肌氨酸聚（N-甲基甘氨酸）引入隐形特性，生成用于 siRNA 递送。静脉注射 siMFAP-5/DES PICM 可显着降低 HCC 同基因植入模型中的肝脏肿瘤负荷，其 MFAP-5 敲低效果优于 siMFAP-5 PICM 或脂质纳米颗粒。转录组和组织学分析表明，MFAP-5 敲低抑制了 CAF 相关的肿瘤血管化，表明 RNA 干扰疗法具有抗血管生成作用。总之，在单个多肽胶束中结合 siMFAP-5 和 DES 的多室 PICM 可诱导 MFAP-5 的特异性敲低，并在临床相关 HCC 模型中表现出有效的抗肿瘤功效（与未治疗的对照相比，肿瘤负荷减少 80%） .© 2024 作者。先进材料由 Wiley‐VCH GmbH 出版。

Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer and the third leading cause for cancer-related death worldwide. The tumor is difficult-to-treat due to its inherent resistance to chemotherapy. Antistromal therapy is a novel therapeutic approach, targeting cancer-associated fibroblasts (CAF) in the tumor microenvironment. CAF-derived microfibrillar-associated protein 5 (MFAP-5) is identified as a novel target for antistromal therapy of HCC with high translational relevance. Biocompatible polypept(o)ide-based polyion complex micelles (PICMs) constructed with a triblock copolymer composed of a cationic poly(l-lysine) complexing anti-MFAP-5 siRNA (siMFAP-5) via electrostatic interaction, a poly(γ-benzyl-l-glutamate) block loading cationic amphiphilic drug desloratatine (DES) via π-π interaction as endosomal escape enhancer and polysarcosine poly(N-methylglycine) for introducing stealth properties, are generated for siRNA delivery. Intravenous injection of siMFAP-5/DES PICMs significantly reduces the hepatic tumor burden in a syngeneic implantation model of HCC, with a superior MFAP-5 knockdown effect over siMFAP-5 PICMs or lipid nanoparticles. Transcriptome and histological analysis reveal that MFAP-5 knockdown inhibited CAF-related tumor vascularization, suggesting the anti-angiogenic effect of RNA interference therapy. In conclusion, multicompartment PICMs combining siMFAP-5 and DES in a single polypept(o)ide micelle induce a specific knockdown of MFAP-5 and demonstrate a potent antitumor efficacy (80% reduced tumor burden vs untreated control) in a clinically relevant HCC model.© 2024 The Author(s). Advanced Materials published by Wiley‐VCH GmbH.