Wu Jiahe, Ma Teng, Zhu Manning, Mu Jiafu, Huang Tianchen, Xu Donghang, Lin Nengming, Gao Jianqing
Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang 310006, China.
Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
ACS Nano. 2024 Feb 9. doi: 10.1021/acsnano.3c12694.
The limited therapeutic outcomes and severe systemic toxicity of chemotherapy remain major challenges to the current clinical antitumor therapeutic regimen. Tumor-targeted drug delivery that diminishes the undifferentiated systemic distribution is a practical solution to ameliorating systemic toxicity. However, the tumor adaptive immune microenvironment still poses a great threat that compromises the therapeutic efficacy of chemotherapy by promoting the tolerance of the tumor cells. Herein, a pluripotential neutrophil-mimic nanovehicle (Neutrosome(L)) composed of an activated neutrophil membrane-incorporated liposome is proposed to modulate the immune microenvironment and synergize antitumor chemotherapy. The prominent tumor targeting capability inherited from activated neutrophils and the improved tumor penetration ability of Neutrosome(L) enable considerable drug accumulation in tumor tissues (more than sixfold that of free drug). Importantly, Neutrosome(L) can modulate the immune microenvironment by restricting neutrophil infiltration in tumor tissue, which may be attributed to the neutralization of inflammatory cytokines, thus potentiating antitumor chemotherapy. As a consequence, the treatment of cisplatin-loaded Neutrosome(L) performs prominent tumor suppression effects, reduces systemic drug toxicity, and prolongs the survival period of tumor-bearing mice. The pluripotential neutrophil-mimic nanovehicle proposed in this study can not only enhance the tumor accumulation of chemotherapeutics but also modulate the immune microenvironment, providing a compendious strategy for augmented antitumor chemotherapy.
化疗有限的治疗效果和严重的全身毒性仍然是当前临床抗肿瘤治疗方案面临的主要挑战。减少非特异性全身分布的肿瘤靶向给药是改善全身毒性的切实可行的解决方案。然而，肿瘤适应性免疫微环境仍然构成巨大威胁，通过促进肿瘤细胞的耐受性来损害化疗的治疗效果。在此，我们提出了一种由活化中性粒细胞膜包裹的脂质体组成的多潜能中性粒细胞模拟纳米载体（Neutrosome(L)），以调节免疫微环境并协同抗肿瘤化疗。Neutrosome(L)继承了活化中性粒细胞显著的肿瘤靶向能力以及改善的肿瘤穿透能力，使得药物在肿瘤组织中大量蓄积（超过游离药物的六倍）。重要的是，Neutrosome(L)可以通过限制中性粒细胞向肿瘤组织浸润来调节免疫微环境，这可能归因于炎性细胞因子的中和作用，从而增强抗肿瘤化疗效果。因此，负载顺铂的Neutrosome(L)治疗具有显著的肿瘤抑制作用，降低全身药物毒性，并延长荷瘤小鼠的生存期。本研究中提出的多潜能中性粒细胞模拟纳米载体不仅可以增强化疗药物在肿瘤中的蓄积，还可以调节免疫微环境，为增强抗肿瘤化疗提供了一种简明的策略。
