It is highly desirable to turn “cold” tumors into “hot” ones to improve the efficacy of antitumor immunotherapy. Herein, we develop the peptide-based small interfering RNA (siRNA) micelleplexes (P^A7R@siPD-L1) for normalizing vascular-immune crosstalk to establish a positive feedback loop in potentiating antitumor immunotherapy. These micelleplexes are equipped with tumor-microenvironment-responsive property for precise drug delivery and release. The prepared P^A7R@siPD-L1-mediated photodynamic therapy could eliminate solid tumors and trigger immunogenic cell death to generate systematic immune responses. Meanwhile, the antiangiogenic peptide A7R normalizes the tumor vasculature by converting chaotic vascular systems into matured and organized ones, thus alleviating tumor hypoxia and promoting intratumoral infiltration by immune cells. Antitumor immunogenicity would be further strengthened with the aid of siPD-L1 by muting the resistance of tumor cells against immune effector cells. This study provides a unique therapeutic strategy in turning “cold” tumors into “hot” tumors enabled by siRNA nanomaterial.

将“冷”肿瘤转变为“热”肿瘤以提高抗肿瘤免疫治疗的疗效是非常可取的。在此，我们开发了基于肽的小干扰 RNA (siRNA) 胶束 ( ^PA7R @siPD-L1)，用于使血管免疫串扰正常化，从而在增强抗肿瘤免疫治疗中建立正反馈回路。这些胶束复合物具有肿瘤微环境响应特性，可用于精确的药物递送和释放。准备好的 P ^A7R@siPD-L1 介导的光动力疗法可以消除实体瘤并引发免疫原性细胞死亡以产生系统性免疫反应。同时，抗血管生成肽 A7R 通过将混乱的血管系统转变为成熟和有组织的系统，使肿瘤血管系统正常化，从而缓解肿瘤缺氧并促进免疫细胞的肿瘤内浸润。在 siPD-L1 的帮助下，通过减弱肿瘤细胞对免疫效应细胞的抗性，将进一步增强抗肿瘤免疫原性。这项研究提供了一种独特的治疗策略，可以通过 siRNA 纳米材料将“冷”肿瘤转变为“热”肿瘤。