Targeted bioorthogonal catalysis holds great potential for localized prodrug activation. Although enantiomerically pure drugs are of vital importance in the clinic, chiral drug synthesis by bioorthogonal reactions in living systems is scarcely reported. Toward this goal, we constructed chirally modified Pd catalysts for the asymmetric transfer hydrogenation (ATH) reaction by using sodium formate as the biocompatible reductant. By combining the ATH reaction and chemotaxis of neutrophil membrane, we achieved inflammation site-selective chiral drug synthesis in living cells. As a proof of concept, we synthesized the chiral model drug ibuprofen in situ by a targeted ATH reaction to alleviate inflammation in the mouse paw as an in vivo model. Compared with controls, the neutrophil-membrane-coated chiral Pd catalysts exhibited inflammation-targeted capability and enantioselectivity simultaneously in the anti-inflammatory action. This study could offer a novel perspective for bioorthogonal catalysis in targeted prodrug activation.

靶向生物正交催化在局部前药活化方面具有巨大潜力。尽管对映体纯药物在临床中至关重要，但几乎没有报道通过生物正交反应在生物体内合成手性药物。为实现这一目标，我们使用甲酸钠作为生物相容性还原剂，构建了用于不对称转移氢化（ATH）反应的手性改性Pd催化剂。通过结合ATH反应和嗜中性粒细胞膜的趋化性，我们实现了活细胞中炎症部位选择性手性药物的合成。作为概念的证明，我们通过靶向性ATH反应原位合成了手性模型药物布洛芬，以减轻体内小鼠爪的炎症模型。与对照相比，中性粒细胞膜包覆的手性钯催化剂在抗炎作用中同时具有靶向炎症的能力和对映选择性。这项研究可以为靶向的前药活化中的生物正交催化提供新的视角。