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.