Glutathione‐Scavenging Nanoparticle‐Mediated PROTACs Delivery for Targeted Protein Degradation and Amplified Antitumor Effects

Abstract

PROteolysis TArgeting Chimeras (PROTACs) are an emerging class of promising therapeutic modalities that selectively degrade intracellular proteins of interest by hijacking the ubiquitin‐proteasome system. However, the lack of techniques to efficiently transport these degraders to targeted cells and consequently the potential toxicity of PROTACs limit their clinical applications. Here, a strategy of nanoengineered PROTACs, that is, Nano‐PROTACs, is reported, which improves the bioavailability of PROTACs and maximizes their capacity to therapeutically degrade intracellular oncogenic proteins for tumor therapy. The Nano‐PROTACs are developed by encapsulating PROTACs in glutathione (GSH)‐responsive poly(disulfide amide) polymeric (PDSA) nanoparticles and show that ARV@PDSA Nano‐PROTAC, nanoengineered BRD4 degrader ARV‐771, improves BRD4 protein degradation and decreases the downstream oncogene c‐Myc expression. Benefiting from the GSH‐scavenging ability to amply the c‐Myc‐related ferroptosis and cell cycle arrest, this ARV@PDSA Nano‐PROTACs strategy shows superior anti‐tumor efficacy with a low dose administration and good biocompatibility in vivo. The findings reveal the potential of the Nano‐PROTACs strategy to treat a broad range of diseases by dismantling associated pathogenic proteins.

In situ Engineering of Tumor‐Associated Macrophages via a Nanodrug‐Delivering‐Drug (β‐Elemene@Stanene) Strategy for Enhanced Cancer Chemo‐Immunotherapy

“…Chemie improve its colloidal stability and aqueous suspension, STNS was coated with a lipid-polyethylene glycol (PEG) layer by resuspension in a solution mixture of 1, 2-distearoyl-snglycero-3-phosphoethanolamine (DSPE-PEG), followed by solvent evaporation and rehydration. [29,30] The engineered nanoparticles, termed STNSP, had an average hydrodynamic diameter (d) of 78 � 7 nm (Figure S1d) and were stable in a physiological environment for 1 week (Figure 1b). Moreover, the successful PEG coating on the surface of STNS was confirmed by zeta potential value (Figure S1e), Fourier transform infrared (FTIR, Figure S1f), and thermogravimetric analysis (TGA, Figure S1g).…”

Nano-PROTACs: state of the art and perspectives

“…In addition, polymeric nanoparticles are simple to prepare, have adjustable physicochemical properties, and can be used to deliver a wide variety of drugs such as small molecules, biological macromolecules, proteins, and nucleic acids. Despite all the advantages mentioned above, studies on polymer nanoparticle-based PROTAC drugs 61,[68][69][70][71][72][73][74][75] are currently facing serious drawbacks for efficient encapsulation of PROTACs, smart delivery systems, and clinical translation. To solve these dilemmas, Liu et al 73 used two synthetic polymers, DSPE-PEG and PDSA, to prepare a biodegradable polymer nanoparticle for BRD4 degrader ARV-771 delivery (Fig.…”

Silicon-containing nanomedicine and biomaterials: materials chemistry, multi-dimensional design, and biomedical application

“…For instance, the TME features an acidic pH, high level of GSH, overexpression of specific enzymes, excessive reactive oxygen species (ROS), and hypoxia, which can act as specific stimuli to trigger the release of drugs. 723 Moreover, MSNs/MONs have also been integrated with other functional components to construct exogenous stimuli-responsive drug delivery systems that respond to light, magnet, US, and X-rays. Given that the stimuli-responsive drug delivery systems based on MSNs/MONs have been systematically reviewed in terms of gatekeepers and stimuli in recent publications, 27,724–726 herein we focus on the fundamental principles for the construction of MSN/MON-based stimuli-responsive drug delivery.…”