Next-generation strategies for PROTAC formulation: mechanistic insights and advanced formulation technologies

INTRODUCTION: Proteolysis-targeting chimeras (PROTAC) are an innovative treatment approach that selectively breaks down disease-relevant proteins by utilizing the ubiquitin-proteasome system. Other than PROTAC, Molecular glue, Lysosome-Targeting Chimaera (LYTAC), GlueTAC, Autophagy-Targeting Chimaera (AUTAC), Autophagosome Tethering Compound (ATTEC), and Antibody-based PROTAC (AbTAC) are emerging targeted protein degradation (TPD) techniques, of which PROTAC offers several benefits. AREAS COVERED: This review discusses the development of proteolysis-targeting chimeras (PROTACs) for targeted protein degradation, highlighting their mechanism of action via the ubiquitin - proteasome system. It examines key physicochemical and pharmacokinetic challenges that limit clinical translation. Advanced formulation strategies, including nanoformulations and amorphous solid dispersions, prodrug improve solubility, bioavailability, and therapeutic efficacy. Additionally, characterization techniques are summarized, and the review outlines recent progress and critical considerations for the successful clinical translation of PROTAC-based therapeutics. Relevant articles from PubMed, Scopus, and Web of Science, spanning publications up to 2026, were gathered. EXPERT OPINION: PROTACs represent a transformative therapeutic modality, enabling selective protein degradation beyond conventional inhibition. Future research should focus on improving bioavailability, targeted delivery, and stability, while advancing prodrug strategies, E3 ubiquitin ligase selectivity, oral formulations, and predictive models for clinical translation. Additionally, it should emphasize scalable manufacturing, regulatory frameworks, and integration with emerging targeted protein degradation technologies.