Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China; National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, 200240, China.
Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China; National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, 200240, China.
Biomaterials. 2025 Jan;312:122745. doi: 10.1016/j.biomaterials.2024.122745. Epub 2024 Aug 3.
Stimulator of interferon genes (STING) agonists have shown promise in cancer treatment by stimulating the innate immune response, yet their clinical potential has been limited by inefficient cytosolic entry and unsatisfactory pharmacological activities. Moreover, aggressive tumors with "cold" and immunosuppressive microenvironments may not be effectively suppressed solely through innate immunotherapy. Herein, we propose a multifaceted immunostimulating nanoparticle (Mn-MC NP), which integrates manganese II (Mn) coordinated photosensitizers (chlorin e6, Ce6) and STING agonists (MSA-2) within a PEGylated nanostructure. In Mn-MC NPs, Ce6 exerts potent phototherapeutic effects, facilitating tumor ablation and inducing immunogenic cell death to elicit robust adaptive antitumor immunity. MSA-2 activates the STING pathway powered by Mn, thereby promoting innate antitumor immunity. The Mn-MC NPs feature a high drug-loading capacity (63.42 %) and directly ablate tumor tissue while synergistically boosting both adaptive and innate immune responses. In subsutaneous tumor mouse models, the Mn-MC NPs exhibit remarkable efficacy in not only eradicating primary tumors but also impeding the progression of distal and metastatic tumors through synergistic immunotherapy. Additionally, they contribute to preventing tumor recurrence by fostering long-term immunological memory. Our multifaceted immunostimulating nanoparticle holds significant potential for overcoming limitations associated with insufficient antitumor immunity and ineffective cancer treatment.
干扰素基因刺激剂（STING）激动剂通过刺激先天免疫反应在癌症治疗中显示出前景，但由于细胞内进入效率低下和不尽如人意的药理活性，其临床潜力受到限制。此外，具有“冷”和免疫抑制微环境的侵袭性肿瘤可能无法仅通过先天免疫疗法有效抑制。在此，我们提出了一种多功能免疫刺激纳米颗粒（Mn-MC NP），它将锰 II（Mn）配位的光敏剂（氯乙酮，Ce6）和 STING 激动剂（MSA-2）整合在聚乙二醇化的纳米结构内。在 Mn-MC NPs 中，Ce6 发挥强大的光疗作用，促进肿瘤消融并诱导免疫原性细胞死亡，引发强大的适应性抗肿瘤免疫。MSA-2 由 Mn 提供动力激活 STING 途径，从而促进先天抗肿瘤免疫。Mn-MC NPs 具有高载药能力（63.42%），可直接消融肿瘤组织，同时协同增强适应性和先天免疫反应。在皮下肿瘤小鼠模型中，Mn-MC NPs 不仅在根除原发性肿瘤方面表现出显著疗效，而且通过协同免疫疗法阻止远端和转移性肿瘤的进展。此外，它们通过促进长期免疫记忆有助于防止肿瘤复发。我们的多功能免疫刺激纳米颗粒具有克服抗肿瘤免疫不足和癌症治疗无效相关限制的巨大潜力。
