Escudé Martinez de Castilla Pol, Verdi Vincenzo, de Voogt Willemijn, Estapé Sentí Mariona, Koekman Arnold C, Rietveld Julian, van Kempen Sven, Yang Qiangbing, van Merris Juliette, Jenster Guido, van Royen Martin E, Fens Marcel H, Kooijmans Sander A A, van Weerden Wytske M, van Niel Guillaume, Vader Pieter, Schiffelers Raymond M
CDL Research, University Medical Center Utrecht, Utrecht, 3584CX, The Netherlands.
Institut de Psychiatrie et Neurosciences de Paris, Université Paris Cité, INSERM 1266, Paris, 75014, France.
Adv Healthc Mater. 2025 Sep;14(24):e2500605. doi: 10.1002/adhm.202500605. Epub 2025 Jul 4.
Prostate cancer (PCa) ranks as the fifth leading cause of cancer-related deaths among men worldwide. In 10-20% of the cases, PCa progresses to an incurable, castration-resistant stage. Castration-resistant PCa cells often overexpress prostate-specific membrane antigen (PSMA), a membrane protein that may serve as their Achilles' heel. Over the past decades, RNA-based therapeutics have emerged as promising treatments for a vast array of diseases, including cancer. In this study, with the ultimate goal of developing a targeted therapy for PCa, lipid nanoparticles (LNPs) are decorated with an anti-PSMA nanobody using click chemistry with a PEG-lipid. Direct stochastic optical reconstruction microscopy (dSTORM) and cluster analysis confirm the presence of at least one nanobody on the surface of 80% of LNPs. These anti-PSMA LNPs exhibit enhanced and specific uptake, and mRNA transfection in PSMA+ cancer cells both in vitro and in a Zebrafish (ZF) metastatic PCa xenograft model. Additionally, in a mouse PSMA-positive xenograft model, systemic administration results in increased LNP accumulation, but not functional mRNA delivery. These findings underscore both the potential and the challenges of using a PSMA-targeted lipid nanoparticle system for mRNA delivery into advanced prostate cancer tumors.
前列腺癌（PCa）是全球男性癌症相关死亡的第五大主要原因。在10%-20%的病例中，PCa会发展到无法治愈的去势抵抗阶段。去势抵抗性PCa细胞通常过度表达前列腺特异性膜抗原（PSMA），这是一种膜蛋白，可能是它们的致命弱点。在过去几十年中，基于RNA的疗法已成为包括癌症在内的多种疾病的有前景的治疗方法。在本研究中，为了开发针对PCa的靶向疗法这一最终目标，利用点击化学将脂质纳米颗粒（LNP）与一种聚乙二醇脂质修饰上抗PSMA纳米抗体。直接随机光学重建显微镜（dSTORM）和聚类分析证实80%的LNP表面至少存在一个纳米抗体。这些抗PSMA LNP在体外和斑马鱼（ZF）转移性PCa异种移植模型中均表现出增强的特异性摄取以及在PSMA+癌细胞中的mRNA转染。此外，在小鼠PSMA阳性异种移植模型中，全身给药导致LNP积累增加，但未实现功能性mRNA递送。这些发现强调了使用PSMA靶向脂质纳米颗粒系统将mRNA递送至晚期前列腺癌肿瘤的潜力和挑战。
