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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. [ABSTRACT FROM AUTHOR]

Even a well‐designed system can only control stem cell adhesion, release, and differentiation, while other cell manipulations such as in situ labeling and retention in target tissues, are difficult to achieve in the same system. Herein, native ligand cluster‐mimicking islands, composed of topologically engineered ligand, anchoring point AuNP, nuclease mimetics CeIV complexes and magnetic core Fe3O4, are designed to facilitate comprehensive cell manipulations in a programmable manner. Three islands with different amounts of AuNPs are constructed, which means tunable interligand spacing within a cluster. These nanostructures are chemically coupled to a substrate using DNA tethers. Under a tissue‐penetrative magnetic field, this integrated system promotes stem cell adhesion, proliferation, mechanosensing, differentiation, detachment, in situ effective magnetic labeling and retention both in vitro and in vivo, offering fascinating opportunities for a biomimetic matrix in regenerative medicine. [ABSTRACT FROM AUTHOR]

Tumor-activatable ultrasmall nanozyme generation is an unprecedented strategy to overcome intrinsically fatal defects of traditional reactive oxygen species (ROS)-based nanoagents for deep tumor penetration, including limited tissue-penetrating depth of external energy, heavy reliance on oxygen and nonspecific toxicity of therapeutic agents. Here, based on the cascade reaction between glucose oxidase (GOx) and ultrasmall peroxidase nanozyme embedded into acid-dissociable zeolitic imidazolate framework-8 (ZIF-8), such a tumor-activatable ultrasmall nanozyme generator is designed for enhanced penetration and deep catalytic therapy. With the aid of mildly acidic tumor microenvironment, the produced gluconic acid from intratumoral glucose can gradually induce the dissociation of ZIF-8 to release ultrasmall peroxidase nanozyme with significant intratumoral penetration. On the other hand, the generated hydrogen peroxide with relatively long-life can be subsequently catalyzed by penetrated peroxidase nanozyme into toxic hydroxyl radicals for deep catalytic therapy. In this way, the well-designed nanoplatform not only can greatly enhance tumor penetration but also directly induce exogenous ROS without oxygen participation and external energy input, thereby thoroughly avoiding the inactivation of traditional ROS-based nanoagents in the extremely hypoxic tumor center and finally resulting in remarkable deep catalytic therapy. [ABSTRACT FROM AUTHOR]