肿瘤细胞治疗研究
英文原题：Pancreatic-targeted lipid nanoparticles based on organ capsule filtration.
实现胰腺靶向递送是治疗胰腺疾病的一项突破，但精准递送仍具挑战性 1。
实现胰腺靶向递送是治疗胰腺疾病的一项突破，但精准递送仍具挑战性1。在此，我们确定了一条明确且通用的胰腺选择性递送原则，并提出了一种用于mRNA递送的胰腺靶向脂质纳米颗粒（AH-LNP）。AH-LNP在与蛋白质组装后尺寸增大，促进胶囊滤器介导的胰腺选择性蓄积和受体介导的内吞作用，从而增强胰腺靶向能力。得益于此，AH-LNP通过递送Cas9 mRNA和单链引导RNA（sgRNA），能够在胰腺中实现精准高效的基因组编辑，在自身免疫性胰腺疾病治疗中展现出良好潜力。此外，通过AH-LNP将编码治疗性细胞因子的mRNA进行胰腺靶向递送，在多种胰腺癌模型中与癌症疫苗或CAR-T 细胞疗法联合使用时，表现出优越的抗肿瘤疗效。AH-LNP的安全性和胰腺mRNA递送已在多种动物模型（包括非人灵长类动物）中得到验证，展现出巨大的临床转化前景。我们的研究结果凸显了这一胰腺靶向机制及由此衍生的LNP平台的变革性潜力，为开发针对多种胰腺疾病的精准疗法开辟了道路。
Achieving pancreatic-targeted delivery marks a breakthrough in treating pancreatic diseases, yet precise delivery remains challenging 1 . Here we identify an explicit and universal principle for pancreatic-selective delivery and propose a pancreatic-targeted lipid nanoparticle (AH-LNP) for mRNA delivery. AH-LNP exhibits size enlargement after assembly with proteins, facilitating capsule-filter-mediated pancreas-selective accumulation and receptor-mediated endocytosis, thereby boosting the pancreatic-targeted ability. Benefiting from this, AH-LNP enables precise and efficient genome editing in the pancreas through the delivery of Cas9 mRNA and single guide RNA (sgRNA), exhibiting promising potential in the treatment of autoimmune pancreatic diseases. Furthermore, pancreatic-targeted delivery of mRNA encoding therapeutic cytokines through AH-LNP demonstrates superior antitumour efficacy when combined with a cancer vaccine or chimeric antigen receptor T cell therapy in multiple pancreatic cancer models. The safety and pancreatic mRNA delivery of AH-LNP were verified in multiple animal models, including non-human primates, demonstrating great promise for clinical translation. Our findings highlight the transformative potential of this pancreatic-targeted mechanism and the derived LNP platform, opening avenues for developing precision therapeutics against diverse pancreatic diseases.
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