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通过自噬调节增强肿瘤温和光热疗法的自驱动智能纳米马达

Self-propelled smart nanomotors for enhanced mild photothermal therapy of tumors through autophagy modulation.

作者信息

Mei Ling, Liu Haowei, Ding Qihang, Xie Yuxin, Shen Xue, Chen Haiyan, Wang Kaixi, Li Man, He Qin

机构信息

Engineering Research Center for Pharmaceuticals and Equipments of Sichuan Province, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu 610106, China.

Department of Chemistry, Korea University, Seoul, 02841, South Korea.

出版信息

Acta Biomater. 2025 Jul 1;201:574-590. doi: 10.1016/j.actbio.2025.05.063. Epub 2025 Jun 4.


DOI:10.1016/j.actbio.2025.05.063
PMID:40480413
Abstract

Mild photothermal therapy (mPTT) holds significant potential as a minimally invasive strategy for tumor ablation. However, its clinical translation remains constrained by the uneven intratumoral distribution of photothermal agents and the induction of autophagy pathways. These limitations frequently culminate in suboptimal therapeutic efficacy, facilitating immune evasion by residual tumor cells and thereby elevating the risk of recurrence and metastasis. Here, we report the development of nitric oxide-driven nanomotors (L-Arg-CaP@PDA-CQ) constructed by encapsulating L-arginine within calcium phosphate nanoparticles, functionalized with poly-dopamine shells and loaded with chloroquine, an autophagy inhibitor. These self-propelled nanomotors demonstrated the ability to evade lysosomal phagocytosis, penetrate vascular barriers, and enhance intratumoral accumulation. Autophagy inhibition sensitized melanoma cells to mPTT, while the combination of chloroquine with mPTT induced reactive oxygen species generation and mitochondrial disruption. Furthermore, mPTT facilitated immunogenic cell death, and chloroquine-mediated inhibition of autophagosome degradation enhanced tumor antigen presentation, stimulating robust T-cell infiltration and immune activation. This dual mechanism significantly suppressed tumor recurrence and metastasis. The proposed nanomotors provide a synergistic paradigm for augmenting mPTT and activating antitumor immunity, highlighting their translational potential in clinical oncology. STATEMENT OF SIGNIFICANCE: Mild photothermal therapy (mPTT) is a promising cancer treatment modality that operates at lower temperatures to minimize damage to healthy tissues while promoting antitumor immune responses. However, its efficacy can be limited by the activation of autophagy in tumor cells, which supports tumor survival. In addition, the hypoxic microenvironment of melanoma tumors often restricts drug penetration, further complicating treatment. To address these challenges, we have designed self-propelled smart nanomotors that can actively penetrate acidic tumor tissues and deliver drugs to the tumor site.These nanomotors modulate autophagy to enhance the sensitivity of melanoma cells to mPTT, leading to efficient tumor cell ablation. When combined with chloroquine, this approach generates large amounts of reactive oxygen species and causes mitochondrial damage, while promoting T-cell infiltration through the release of damage-associated molecular patterns (DAMPs). This strategy not only enhances the therapeutic efficacy of mPTT but also holds significant potential for clinical translation in the treatment of melanoma.

摘要

温和光热疗法(mPTT)作为一种肿瘤消融的微创策略具有巨大潜力。然而,其临床应用仍受光热剂在肿瘤内分布不均以及自噬途径诱导的限制。这些限制常常导致治疗效果欠佳,促使残余肿瘤细胞逃避免疫监视,从而增加复发和转移风险。在此,我们报道了通过将L-精氨酸封装于磷酸钙纳米颗粒中构建的一氧化氮驱动纳米马达(L-Arg-CaP@PDA-CQ),其表面用聚多巴胺壳层功能化并负载自噬抑制剂氯喹。这些自驱动纳米马达展现出逃避溶酶体吞噬、穿透血管屏障以及增强肿瘤内蓄积的能力。自噬抑制使黑色素瘤细胞对mPTT敏感,而氯喹与mPTT联合可诱导活性氧生成和线粒体破坏。此外,mPTT促进免疫原性细胞死亡,氯喹介导的自噬体降解抑制增强肿瘤抗原呈递,刺激强大的T细胞浸润和免疫激活。这种双重机制显著抑制肿瘤复发和转移。所提出的纳米马达为增强mPTT和激活抗肿瘤免疫提供了一种协同模式,凸显了其在临床肿瘤学中的转化潜力。重要性声明:温和光热疗法(mPTT)是一种有前景的癌症治疗方式,在较低温度下运作以尽量减少对健康组织的损伤,同时促进抗肿瘤免疫反应。然而,其疗效可能受肿瘤细胞中自噬激活的限制,自噬支持肿瘤存活。此外,黑色素瘤肿瘤的缺氧微环境常常限制药物渗透,使治疗更加复杂。为应对这些挑战,我们设计了可主动穿透酸性肿瘤组织并将药物递送至肿瘤部位的自驱动智能纳米马达。这些纳米马达调节自噬以增强黑色素瘤细胞对mPTT的敏感性,从而实现高效肿瘤细胞消融。与氯喹联合使用时该方法可产生大量活性氧并导致线粒体损伤,同时通过释放损伤相关分子模式(DAMPs)促进T细胞浸润。此策略不仅增强了mPTT的治疗效果,在黑色素瘤治疗的临床转化方面也具有巨大潜力。

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