大约三分之一的人类癌症编码异常的 RAS 蛋白，这些蛋白锁定在组成性激活状态，以驱动恶性转化和不受控制的肿瘤生长。尽管在治疗突变 KRAS 癌症的小分子开发方面取得了进展，但仍然需要一种能够有效对抗所有 RAS 亚型和变体并避免耐药性的泛 RAS 抑制剂。我们之前已经证明，天然存在的细菌酶 RAS/RAP1 特异性内肽酶 (RRSP) 是一种有效的 RAS 降解剂，可以将其重新设计为一种生物疗法，以诱导结直肠癌、乳腺癌和胰腺肿瘤的消退。在这里，我们开发了一种通过 mRNA 递送体内表达该 RAS 降解剂的策略，使用由聚（乙二醇）-b-聚（丙烯硫醚）（PEG-b-PPS）嵌段共聚物组成的合成非病毒基因递送平台与树突状阳离子肽 (PPDP2) 缀合。使用这种策略，PPDP2 可将 mRNA 递送至人和小鼠胰腺细胞，导致 RRSP 基因表达、活性和细胞增殖丧失。此外，胰腺肿瘤减少，残留肿瘤缺乏可检测到的 RAS 和磷酸化 ERK。这些数据支持 RAS 降解剂的 mRNA 负载合成纳米载体递送可以中断胰腺癌细胞内的 RAS 信号系统，同时避免治疗期间的副作用。

About one-third of all human cancers encode abnormal RAS proteins locked in a constitutively activated state to drive malignant transformation and uncontrolled tumor growth. Despite progress in development of small molecules for treatment of mutant KRAS cancers, there is a need for a pan-RAS inhibitor that is effective against all RAS isoforms and variants and that avoids drug resistance. We have previously shown that the naturally occurring bacterial enzyme RAS/RAP1-specific endopeptidase (RRSP) is a potent RAS degrader that can be re-engineered as a biologic therapy to induce regression of colorectal, breast, and pancreatic tumors. Here, we have developed a strategy for in vivo expression of this RAS degrader via mRNA delivery using a synthetic nonviral gene delivery platform composed of the poly(ethylene glycol)-b-poly(propylene sulfide) (PEG-b-PPS) block copolymer conjugated to a dendritic cationic peptide (PPDP2). Using this strategy, PPDP2 is shown to deliver mRNA to both human and mouse pancreatic cells resulting in RRSP gene expression, activity, and loss of cell proliferation. Further, pancreatic tumors are reduced with residual tumors lacking detectable RAS and phosphorylated ERK. These data support that mRNA-loaded synthetic nanocarrier delivery of a RAS degrader can interrupt the RAS signaling system within pancreatic cancer cells while avoiding side effects during therapy.