Engineered probiotics are an emerging platform for in situ delivery of therapeutics to the gut. Herein, we developed an orally administered, yeast-based therapeutic delivery system to deliver next-generation immune checkpoint inhibitor (ICI) proteins directly to gastrointestinal tumors. We engineered Saccharomyces cerevisiae var. boulardii (Sb), a probiotic yeast with high genetic tractability and innate anticancer activity, to secrete “miniature” antibody variants that target programmed death ligand 1 (Sb_haPD-1). When tested in an ICI-refractory colorectal cancer (CRC) mouse model, Sb_haPD-1 significantly reduced intestinal tumor burden and resulted in significant shifts to the immune cell profile and microbiome composition. This oral therapeutic platform is modular and highly customizable, opening new avenues of targeted drug delivery that can be applied to treat a myriad of gastrointestinal malignancies.

中文翻译：

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一种基于酵母的口服治疗药物提供免疫检查点抑制剂以减轻肠道肿瘤负荷


工程益生菌是将治疗药物原位递送至肠道的新兴平台。在此，我们开发了一种口服的、基于酵母的治疗递送系统，可将下一代免疫检查点抑制剂 （ICI） 蛋白直接递送到胃肠道肿瘤。我们设计了酿酒酵母变种布拉氏菌 （Sb），一种具有高遗传易处理性和先天抗癌活性的益生菌酵母，以分泌靶向程序性死亡配体 1 （Sb_haPD-1） 的“微型”抗体变体。在 ICI 难治性结直肠癌 （CRC） 小鼠模型中进行测试时，Sb_haPD-1 显著降低了肠道肿瘤负荷，并导致免疫细胞谱和微生物组组成的显着变化。该口服治疗平台是模块化且高度可定制的，开辟了靶向给药的新途径，可用于治疗无数胃肠道恶性肿瘤。