Chirality-Dependent Reprogramming of Macrophages by Chiral Nanozymes

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 MoS₂ /CoS₂ 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. MoS₂ /CoS₂ 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 (O₂ ) 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.