Degraders on Demand: Engineering Smart Nanocarriers for PROTAC Delivery.

Proteolysis-targeting chimeras (PROTACs) are transforming targeted therapeutics by enabling the selective and catalytic degradation of disease-associated proteins, offering new treatment avenues in oncology, neurodegeneration, immunology, and infectious diseases. However, their clinical translation is limited by poor membrane permeability, low oral bioavailability, suboptimal pharmacokinetics, a narrow range of useable E3 ligases, emerging resistance mechanisms, and safety concerns associated with their use. Nanocarrier-based delivery systems, including liposomes, polymeric nanoparticles, dendrimers, exosomes, and metal-organic frameworks, have emerged as promising solutions to these challenges. By enhancing solubility, protecting PROTACs from enzymatic degradation, improving cellular uptake, and enabling controlled stimuli-responsive release, nanocarriers can significantly improve pharmacological performance and tumor accumulation and reduce off-target toxicity. This review critically explores the intersection of PROTAC technology and nanocarrier-enabled delivery, summarizes key physicochemical and biological barriers, highlights recent advances in nanocarrier design and preclinical applications, and discusses the integration of artificial intelligence in rational PROTAC development. The persistent challenges of endosomal escape, tumor heterogeneity, immunogenicity, and regulatory hurdles were addressed, and future directions were proposed for optimizing nanoenabled PROTAC therapies to fully realize their clinical potential.