肿瘤细胞治疗研究
英文原题：Biodegradable targeted polymeric mRNA nanoparticles enable in vivo CD19 CAR T cell generation and lead to B cell depletion.
这些纳米颗粒能够灵活地包裹 mRNA 货物，并在体内用于递送 anti-CD19 CAR mRNA，从而在健康小鼠中实现外周血中 95% 的 B 细胞清除和脾脏 B 细胞的 50% 清除。
尽管嵌合抗原受体 (CAR) T 细胞疗法已显示出对 B 细胞恶性肿瘤的治疗疗效，但这些疗法的广泛应用受到繁琐的离体生产过程的阻碍。将编码 CAR 的信使 RNA (mRNA) 递送至内源性 T 细胞可在体内生成这些治疗性细胞，并简化该生产流程。为实现这一点，将 T 细胞激活配体偶联至可生物降解的聚合物 mRNA 纳米颗粒，以形成 T 细胞靶向颗粒。通过偶联多种激活配体，体外 T 细胞转染和刺激增加，并且与未靶向颗粒相比，实现了更高的体内 T 细胞转染和选择性。这些纳米颗粒能够灵活包封 mRNA 载荷，并用于在体内递送抗 CD19 CAR mRNA，从而使健康小鼠外周血中 95% 的 B 细胞耗竭，并耗竭 50% 的脾脏 B 细胞。这些关于纳米颗粒趋向性及其潜在治疗疗效的发现，凸显了这种非病毒聚合物平台在解决当前 CAR T 实践相关关键局限性方面的重要性。
While chimeric antigen receptor (CAR) T cell therapies have demonstrated therapeutic efficacy against B cell malignancies, widespread implementation of these therapies is hindered by a cumbersome, ex vivo manufacturing process. Delivery of CAR-encoding messenger RNA (mRNA) to endogenous T cells can generate these therapeutic cells in vivo and streamline this manufacturing workflow. To accomplish this, T cell-activating ligands were conjugated to a biodegradable polymeric mRNA nanoparticle to form T cell-targeted particles. By conjugating multiple activating ligands, T cell transfection and stimulation in vitro was increased, and greater T cell transfection and selectivity in vivo was achieved compared to an untargeted particle. These nanoparticles can flexibly encapsulate mRNA cargos and were used to deliver anti-CD19 CAR mRNA in vivo, enabling depletion of 95% of B cells in the peripheral blood and 50% depletion of splenic B cells in healthy mice. These findings regarding nanoparticle tropism and their potential therapeutic efficacy highlight the importance of this nonviral, polymeric platform to address key limitations associated with current CAR T practices.
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