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PROTAC Delivery Strategies for Overcoming Physicochemical Properties and Physiological Barriers in Targeted Protein Degradation

Syahputra, Endry Wahyu, Lee, Hyunji, Cho, Hyukjun, Park, Hyun Jin, Park, Kwang-Su, Hwang, Duhyeong·2025·Pharmaceutics
DOI 10.3390/pharmaceutics17040501PMC PMC12030311
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Abstract

Proteolysis targeting chimeras (PROTACs), heterobifunctional molecules that hijack the ubiquitin–proteasome system (UPS) to degrade specific proteins, hold great promise in treating diseases driven by traditionally “undruggable” targets. However, their large molecular weight, high hydrophobicity, and other physicochemical hurdles contribute to their limited bioavailability, suboptimal pharmacokinetics, and attenuated therapeutic efficacy. Consequently, diverse formulation innovations have been investigated to optimize PROTAC delivery. This review examines current challenges and advances in specialized drug delivery approaches designed to bolster PROTAC pharmacological performance. We first outline the fundamental limitations of PROTACs—their low aqueous solubility, poor cell permeability, rapid clearance, and concentration-dependent “hook effect”. We then discuss how various enabling formulations address these issues, including polymeric micelles, emulsions, amorphous solid dispersions, lipid-based nanoparticles, liposomes, and exosomes. Collectively, these delivery technologies substantially improve the therapeutic outcomes of PROTACs in preclinical cancer models. Future applications may extend beyond oncology to address other complex diseases using newly emerging heterobifunctional molecules. By integrating advanced formulation science with innovative degrader design, the field stands poised to unlock the clinical potential of PROTACs for protein degradation therapies.

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  • Off-target degradation in non-target VHL-expressing tissues remains a potential concern, necessitating careful optimization of dosing strategies and linker chemistry.

    “Despite these advances, off-target degradation in non-target VHL-expressing tissues remains a potential concern, necessitating careful optimization of dosing strategies and linker chemistry96.”

    From Emerging strategies in senotherapeutics: from broad-spectrum senolysis to precision reprogramming (2026) · cites this paper as [96]

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Metadata

Authors
Syahputra, E. W., Lee, H., Cho, H., Park, H. J., Park, K.-S., & Hwang, D.
Venue
Pharmaceutics
Publisher
MDPI AG
Published
2025-04-09
Volume
17
Issue
4
Pages
501
ISSN
1999-4923
DOI
10.3390/pharmaceutics17040501
PMC
PMC12030311
Cited by
88
References
12
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
Korea government (MSIT) (RS-2023-00210769, RS-2023-00214691, RS-2024-00407053, RS-2024-00406114)

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