Proteolysis-targeting chimera (PROTAC) nanomedicines toward cancer treatment: From synthesis to therapeutic delivery

Abstract

Proteolysis-targeting chimera (PROTAC) has emerged as a groundbreaking therapeutic strategy by hijacking the endogenous ubiquitin proteasome system (UPS) for targeted protein degradation. These heterobifunctional molecules recruit E3 ligases to recognize the protein of interest (POI) and facilitate its ubiquitination, leading to subsequent proteasomal degradation. Compared to conventional protein inhibitors, PROTACs offer a broader range of target degradation and remain effective even against proteins with drug-resistant mutations. Moreover, PROTACs function in a catalytic manner to degrade POIs, allowing for significantly lower administration dosages. In recent years, PROTACs have shown great promise in cancer therapy due to their high efficiency and broad applicability. However, their clinical applications remain challenging due to low bioavailability, limited tumor-targeting ability, and potential side effects. Utilizing nanomedicine for the delivery of PROTACs offers a promising strategy to enhance bioavailability, improve tumor selectivity, and minimize toxicity, thereby advancing their applications in cancer treatment. In this review, we outline the fundamental design principles of PROTACs, summarize the latest progress of nanomedicines from molecular design to drug delivery for improved tumor treatment, introduce PROTAC-based combination therapies and emerging design strategies, and discuss current challenges and future prospects of PROTAC nanomedicines toward clinical translation. Proteolysis-targeting chimeras (PROTACs) have garnered increasing attention in cancer treatment due to their exceptional protein degradation efficacy. However, their clinical applications are hindered by challenges such as low bioavailability, limited tumor-targeting capability, and potential off-target effects. The rational design of PROTAC-based nanomedicines holds great promise for overcoming these limitations and advancing their clinical translation. [Display omitted] •This review illustrates the design principles and delivery strategies of PROTACs.•This review highlights the latest advancement of PROAC-based synergistic therapies and novel PROTAC design strategies.•This review summarizes the key challenges and discusses future research direction of PROTAC nanomedicines