Exosome‐Mediated Delivery of PROTACs for Targeted Protein Degradation in Cancer, Neurodegenerative, Infectious, and Inflammatory Diseases
Proteolysis‐targeting chimeras (PROTACs) are heterobifunctional molecules that hijack the ubiquitin‐proteasome system to drive catalytic, sub‐stoichiometric degradation of disease‐associated proteins, offering a mechanistic advantage over occupancy‐driven inhibitors and access to ‘undruggable’ targets. However, their clinical translation is constrained by high molecular weight, poor solubility, low oral bioavailability, inefficient membrane permeability, nonspecific biodistribution, off‐target degradation, and the concentration‐dependent ‘hook effect.’ Exosomes, nanoscale extracellular vesicles with innate biocompatibility, low immunogenicity, prolonged circulation, and the ability to cross barriers such as the blood–brain barrier, offer a biologically integrated platform to overcome these limitations. This review traces the evolution of PROTAC technology, delineates the challenges of conventional delivery, and evaluates the rationale for exosomal encapsulation, including cargo protection, intracellular trafficking, endosomal escape, and release kinetics. We examine natural and engineered exosomes spanning source selection, active loading strategies, and surface functionalization for tissue‐specific homing and synthesize therapeutic applications across viral infections, cancer, neurodegenerative disorders, and inflammatory diseases. Proof‐of‐concept studies, such as camel milk‐derived exosomes delivering the BRD4‐targeting PROTAC ARV‐825, demonstrate enhanced permeability, lower IC50 values, and improved oral bioavailability. Finally, we discuss key hurdles to clinical translation: scalable production, purification, and standardization, and outline future directions for exosome‐mediated targeted protein degradation.