Proteolysis Targeting Chimeras (PROTACs) based on celastrol induce multiple protein degradation for triple-negative breast cancer treatment.

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.

CES1-Triggered Liver-Specific Cargo Release of CRISPR/Cas9 Elements by Cationic Triadic Copolymeric Nanoparticles Targeting Gene Editing of PCSK9 for Hyperlipidemia Amelioration.

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.

Self-Assembling Porphyrins as a Single Therapeutic Agent for Synergistic Cancer Therapy: A One Stone Three Birds Strategy.

Combining photodynamic therapy (PDT), chemodynamic therapy (CDT), and ferroptosis is a valuable means for an enhanced anticancer effect. However, traditional combination of PDT/CDT/ferroptosis faces several hurdles, including excess glutathione (GSH) neutralization and preparation complexity. In this work, a versatile multifunctional nanoparticle (HCNP) self-assembled from two porphyrin molecules, chlorin e6 and hemin, is developed. The as-constructed HCNPs exhibit a peroxidase-mimic catalytic activity, which can lead to the in situ generation of endogenous O2, thereby enhancing the efficacy of PDT. Furthermore, the generation of hydroxyl radicals (•OH) in the tumor environment in reaction to the high level of H2O2 and the simultaneous disruption of intracellular GSH endow the HCNPs with the capacity of enhanced CDT, resulting in a more effective therapeutic outcome in combination with PDT. More importantly, GSH depletion further leads to the inactivation of GSH peroxide 4 and induced ferroptosis. Both in vitro and in vivo results showed that the combination of PDT/CDT/ferroptosis realizes highest antitumor efficacy significantly under laser irradiation. Therefore, by integrating the superiorities of O2 and •OH generation capacity, GSH-depletion effect, and bioimaging into a single nanosystem, the HCNPs are a promising single therapeutic agent for tumor PDT/CDT/ferroptosis combination therapy.

Theranostics of atherosclerosis by the indole molecule-templated self-assembly of probucol nanoparticles.

Atherosclerosis (AS) is a major cause of cardiovascular diseases, but its effective theranostic measure remains challenging thus far. Macrophages contribute to AS progress in diverse ways such as producing cytokines and reactive oxygen species (ROS), foaming macrophages, and differentiating into pro-inflammatory macrophages. With the aim of constructing a facile and efficacious theranostic system for diagnosis and treatment of AS, a templated self-assembly approach was developed. This strategy involves using indole molecule (indocyanine green (ICG) or IR783) as a template to assemble with probucol (PB) to gain multifunctional nanoparticles (IPNPs or IRPNPs). IPNPs and IRPNPs both showed excellent physicochemical properties, which testified the generality of the indole molecular self-assembly strategy for PB delivery. Besides, the nanoparticles have superior pharmaceutical characteristics including preventing macrophages from differentiating, more efficiently internalizing in inflammatory macrophages, eliminating overproduced ROS, lowering the level of inflammation cytokines, and inhibiting foaming. More importantly, IPNPs displayed effective therapeutic effects in AS model mice when administered via intravenous (i.v.) route. In addition, IPNPs and IRPNPs accumulated more effectively than ICG and IR783 via i.v. injection in the lesion area, and the blood circulation time was extended beyond 24 h. More interestingly, we discovered that the fluorescence imaging ability of IR783 and IRPNPs was more excellent than ICG and IPNPs, respectively. Moreover, a long-term treatment with IPNPs or IRPNPs revealed an excellent safety profile in mice. Accordingly, this self-assembly strategy developed herein is a universal and promising way for the delivery of lipophilic drugs. This study also provides new insights into developing effective theranostic agents for AS.