Chen Minglong, Yang Dan, Sun Ying, Liu Ting, Wang Wenhao, Fu Jintao, Wang Qingqing, Bai Xuequn, Quan Guilan, Pan Xin, Wu Chuanbin
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
College of Pharmacy, Jinan University, Guangzhou 510632, China.
ACS Nano. 2021 Feb 23;15(2):3387-3401. doi: 10.1021/acsnano.0c10396. Epub 2021 Feb 12.
Although certain therapeutic agents with immunogenic properties may enhance antitumor immunity, cancer cells can eliminate harmful cytoplasmic entities and escape immunosurveillance by orchestrating autophagy. Here, an ingenious self-assembled nanomicelle dissolving microneedle (DMN) patch was designed for intralesional delivery of immunogenic cell death-inducer (IR780) and autophagy inhibitor (chloroquine, CQ) coencapsulated micelles (C/I-Mil) for efficient antitumor therapy. Upon insertion into skin, the self-assembled C/I-Mil was generated, followed by electrostatic binding of hyaluronic acid, the matrix material of DMNs, accompanied by the dissolution of DMNs. Subsequently, photothermal-mediated size-tunable C/I-Mil could effectively penetrate into deep tumor tissue and be massively internalized CD44 receptor-mediated endocytosis, precisely ablate tumors with the help of autophagy inhibition, and promote the release of damage-associated molecular patterns. Moreover, CQ could also act as an immune modulator to remodel tumor-associated macrophages toward the M1 phenotype activating NF-κB. results showed that the localized photoimmunotherapy in synergy with autophagy inhibition could effectively eliminate primary and distant tumors, followed by a relapse-free survival of more than 40 days remodeling the tumor immunosuppressive microenvironment. Our work provides a versatile, generalizable framework for employing self-assembled DMN-mediated autophagy inhibition integrated with photoimmunotherapy to sensitize superficial tumors and initiate optimal antitumor immunity.
尽管某些具有免疫原性的治疗药物可能会增强抗肿瘤免疫力，但癌细胞可以通过自噬来清除有害的细胞质成分并逃避免疫监视。在此，设计了一种巧妙的自组装纳米胶束溶解微针（DMN）贴片，用于瘤内递送共封装免疫原性细胞死亡诱导剂（IR780）和自噬抑制剂（氯喹，CQ）的胶束（C/I-Mil），以实现高效的抗肿瘤治疗。插入皮肤后，自组装的C/I-Mil生成，随后是DMN的基质材料透明质酸的静电结合，同时DMN溶解。随后，光热介导的尺寸可调C/I-Mil可有效穿透深层肿瘤组织，并通过CD44受体介导的内吞作用大量内化，在自噬抑制的帮助下精确消融肿瘤，并促进损伤相关分子模式的释放。此外，CQ还可作为免疫调节剂，通过激活NF-κB将肿瘤相关巨噬细胞重塑为M1表型。结果表明，与自噬抑制协同作用的局部光免疫疗法可有效消除原发性和远处肿瘤，随后实现超过40天的无复发生存，重塑肿瘤免疫抑制微环境。我们的工作为采用自组装DMN介导的自噬抑制与光免疫疗法相结合以增敏浅表肿瘤并启动最佳抗肿瘤免疫提供了一个通用的框架。
