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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]

In recent years, mRNA‐based therapeutics have been a fast‐growing new class of biologics that can, in principle, encode any protein(s) directly in patients to treat various diseases. mRNA vaccines have been proven to work efficiently, have high potency, and can be rapidly developed and deployed, which is critical for a quick responses in the case of a pandemic. Such agile development is enabled by rapid synthesis of RNA in vitro using recombinant enzymes rather than relying on lengthy and complex cell culture processes. mRNA exhibits physical and chemical properties differing from protein‐based therapeutics. It is highly negatively charged and the hydroxyl group makes mRNA less stable and more susceptible to hydrolysis and nucleophilic cleavage. This novel work shares comprehensive studies carried out to compare the performance of various mRNA purification strategies by considering its scalability and critical quality attributes. In addition, the paper provides insights on how to establish a scalable mRNA purification process that consists of ultrafiltration/diafiltration and chromatography steps with good recoveries. Alternative Oligo(dT) based columns were further explored aiming to improve total process recovery. With Oligo(dT) as a capture step, overall recoveries of 70% can be achieved for mRNAs studied here that encode anti‐influenza immunoglobulin G monoclonal antibodies. [ABSTRACT FROM AUTHOR]

Chemodynamic therapy (CDT), which employs intracellular H 2 O 2 to produce toxic hydroxyl radicals to kill cancer cells, has received great attention due to its specificity to tumors. However, the relatively insufficient endogenous H 2 O 2 and the short-lifetime and limited diffusion distance of •OH compromise the therapeutic efficacy of CDT. Mitochondria, which play crucial roles in oncogenesis, are highly vulnerable to elevated oxidative stress. Herein, we constructed a mitochondria-mediated self-cycling system to achieve high dose of •OH production through continuous H 2 O 2 supply. Cinnamaldehyde (CA), which can elevate H 2 O 2 level in the mitochondria, was loaded in Cu(II)-containing metal organic framework (MOF), termed as HKUST-1. After actively targeting mitochondria, the intrinsic H 2 O 2 in mitochondria of cancer cells could induce degradation of MOF, releasing the initial free CA. The released CA further triggered the upregulation of endogenous H 2 O 2 , resulting in the subsequent adequate release of CA and the final burst growth of H 2 O 2. The cycle process greatly promoted the Fenton-like reaction between Cu2+ and H 2 O 2 and induced long-term high oxidative stress, achieving enhanced chemodynamic therapy. In a word, we put forward an efficient strategy for enhanced chemodynamic therapy. • A mitochondria-specific nanoreactor is constructed for chemodynamic therapy. • The self-cycling nanoreactor enables continuous supply of H 2 O 2 to produce ROS. • The uninterrupted oxidative damage of mitochondria achieves enhanced efficiency. [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]