Chirality‐Dependent Reprogramming of Macrophages by Chiral Nanozymes

Abstract It is known that extracellular free radical reactive oxygen species (ROS) rather than intracellular ROS plays a non‐substitutable role in regulation of tumor‐suppressing (M1) tumor‐associated macrophages (TAMs) polarization. However, most therapeutic nanoplatforms mainly provide intracellular ROS and exhibit insufficient accumulation near TAMs, which strongly limits the macrophage‐based immunotherapeutic effects. Here we design and synthesize chiral MoS 2 /CoS 2 nanozymes with peroxidase (POD)‐like and catalase (CAT)‐like activities to efficiently modulate TAMs polarization and reverse tumor immunosuppression by harnessing their chirality‐specific interactions with biological systems. MoS 2 /CoS 2 nanoparticles coordinated with d ‐chirality ( d ‐NPs, right‐handed) show improved pharmacokinetics with longer circulating half‐life and higher tumor accumulation compared with their l ( left‐handed)‐ and dl ( racemate)‐counterparts. Further, d ‐NPs can escape from macrophage uptake in the tumor microenvironment (TME) with the aid of cell‐unpreferred opposite chirality and act as extracellular hydroxyl radicals (⋅OH) and oxygen (O 2 ) generators to efficiently repolarize TAMs into M1 phenotype. On the contrary, l ‐NPs showed high cellular uptake due to chirality‐driven homologous adhesion between l ‐NPs and macrophage membrane, leading to limited M1 polarization performance. As the first example for developing chiral nanozymes as extracellular‐localized ROS generators to reprogram TAMs for cancer immunotherapy, this study opens an avenue for applications of chiral nanozymes in immunomodulation.