With the extensive development of nanozymes in recent years, catalytic efficiency has been considered as the Gordian knot that restricts the further applications of nanozyme. Moreover, the usage of layered double hydroxides (LDHs) as antioxidant nanozymes for scavenging reactive oxygen species (ROS) has not been studied. Herein, we report a vacancies-rich monolayer cobalt-alumina LDH nanosheet (m-CoAl-LDH) through a facile direct synthesis method as an efficient nanozyme with superoxide dismutase (SOD)-like activity. The m-CoAl-LDH exhibits a record-breaking catalytic efficiency with the catalytic constant (K_cat) as high as 4.33 × 10¹¹ M⁻¹s⁻¹. Elucidated by the experimental and theoretical studies, the abundant oxygen and metal vacancies were existed in the single layer for the outstanding performance owing to the increased active sites. In addition, density functional theory (DFT) calculations further reveal the significant role of synergistic effect of oxygen and metal vacancies in reducing the adsorption energy of superoxide (O₂⁻), which improves the catalytic performance. The m-CoAl-LDH nanosheets were applied in cells to relieving the oxidative damage caused by O₂⁻ in mitochondria. Such vacancy-rich monolayer CoAl-LDH nanosheets represent the first example of LDH nanozyme with specific SOD-like activity as well as record high catalytic efficiency, which may provide deeper insight into efficient nanozyme design by defect-engineering.

The pursuit of single drugs targeting multiple targets has become a prominent trend in modern cancer therapeutics. Natural products, known for their multi-targeting capabilities, accessibility, and cost-effectiveness, hold great potential for the development of multi-target drugs. However, their therapeutic efficacy is often hindered by complex structural modifications and limited anti-tumor activity. In this study, we present a novel approach using celastrol (CST)-based Proteolysis Targeting Chimeras (PROTACs) for breast cancer therapy. Through rational design, we have successfully developed compound 6a, a potent multiple protein degrader capable of selectively degrading GRP94 and CDK1/4 in tumor cells via the endogenous ubiquitin-proteasome system. Furthermore, compound 6a has demonstrated remarkable inhibitory effects on cell proliferation and migration, and induction of apoptosis in 4T1 cells through cell cycle arrest and activation of the Bcl-2/Bax/cleaved Caspase-3 apoptotic pathway. In vivo administration of compound 6a has effectively suppressed tumor growth with an acceptable safety profile. Our findings suggest that the CST-based PROTACs described herein can be readily extended to other natural products, offering a potential avenue for the development of natural product-based PROTACs for cancer treatment.

The broad application of clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 genome editing tools is hindered by challenges in the efficient delivery of its two components into specific cells and intracytoplasmic release. Herein, a novel copolymer for delivery of Cas9‐mRNA/ single‐guide RNA (Cas9‐mRNA/sgRNA) in vitro and vivo, using carboxylesterase‐responsive cationic triadic copolymeric nanoparticles targeted proprotein convertase subtilisin/kexin type 9 (PCSK9) for hyperlipidemia amelioration is reported. A dimethyl biguanide derivative is designed and synthesized to form cationic block, and copolymerization onto prepolymer with propyl methacrylate, to fabricate a triadic copolymer mPEG‐b‐P(Met/n‐PMA). The copolymer can self‐assemble with Cas9‐mRNA/sgRNA, indicating the excellent potential of nanoparticles to form a delivery carrier. This vehicle can efficiently release RNA in response to the hepatocytes carboxylesterase for genome editing. It was demonstrated that the mPEG‐b‐P(Met/n‐PMA)/Cas9 mRNA/sgRNA nanoparticles effectively accumulated in hepatocytes, lead to the inhibition of PCSK9, and lowered the levels of Low‐density lipoprotein cholesterol and total cholesterol in mouse serum down 20% of nontreatment. Interestingly, the nanoparticles even enable multiple functions in the regulation of blood glucose and weight. This study establishes a novel method to achieve complex CRISPR components stable loading, safe delivery, and fixed‐point release, which expand the application of CRISPR delivery systems.

Rationale: Challenges such as developing a universal tumor-specific probe for tumor margin identification in diverse tumors with an easy-operative and fast-imaging pattern still exist. Hence, in the present study, a rapidly “off-on” near-infrared (NIR) fluorescent probe NBD with pH-activatable fluorescence and a large Stokes shift was constructed for spray mediated near-instant and precise clinical tumor margins identification.