Jul 2026· Journal of Cellular and Molecular Medicine· Vol 30· 0 citations· 71 references
Medicine
TL;DR
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 and outlines future directions for exosome‐mediated targeted protein degradation.
Abstract
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.
Proteolysis‐targeting chimeras (PROTACs) are promising therapeutic agents for targeted protein degradation via the ubiquitin‐proteasome system; however, their clinical application is severely constrained by poor membrane permeability due to high molecular weight and polar surface area, limiting passive diffusion. Emerging evidence suggests that receptor‐mediated endocytosis within tumor microenvironments provides an alternative and potentially generalizable entry route for PROTAC delivery independent of classical diffusion. This review proposes a systematic framework for tumor endocytosis‐guided PROTAC delivery, centered on the identification and exploitation of endocytic biomarkers. A three‐tiered screening strategy is established based on tumor‐selective expression, validated internalization capacity, and functional relevance to tumor dependency. Using this framework, nine representative biomarkers are evaluated with respect to endocytic pathways, intracellular trafficking fate, and delivery suitability. Furthermore, we present a unified PROTAC engineering strategy matrix integrating ligand design, cleavable linker chemistry, and endosomal escape modules to align with receptor‐specific trafficking behaviors. A multiscale validation pipeline covering binding, internalization, intracellular release, and in vivo pharmacodynamics is also outlined. Collectively, this review establishes tumor endocytic pathways as programmable delivery interfaces, providing a rational roadmap for next‐generation PROTAC design with improved efficiency and translational potential.
Hua-Hua Chen, Jiayan Jiao, Huiling Yang et al.· MedComm – Biomaterials and A...· 0 citations
This review systematically outlines design and construction strategies for in situ self-assembling PROTACs with recent advances in nanodelivery systems that improve solubility, bioavailability, and degradation efficacy while mitigating off-target effects and the hook effect.
Pan Liang, Yuying Ren, Yongning Bian et al.· Chemical Communications· 0 citations
Targeted protein degradation (TPD) represents a whole new paradigm in cell-level therapeutic design, with its ability to remove target proteins, normally through the endogenous proteasomal, lysosomal, or autophagic systems, rather than the traditional occupancy-driven inhibition approach. But the clinical efficacy of degraders is becoming more restricted based on delivery rather than efficacy only. Many proteolysis-targeting chimeras and new proximity-inducing systems have low solubility, are impermeable, are pharmacodynamically complicated, lack tissue selectivity, and cannot fully access the intracellular space. Nanomedicine and PD platforms could provide strategies not only to overcome these challenges, but also to provide other advantages, including enhancing exposure to degraders, biodistribution, controlled release, and context-dependent activation. This critical review is an outline of all lipid, polymeric, inorganic, biomimetic, targeted, activatable, and self-assembling delivery systems for TPD. We assess compositional considerations, in vitro and in vivo evidence, challenges for translation, and clinical endpoints required to support delivery-enabled degradation. Trusted TPD therapeutics need to relate different aspects of their design, such as degrader chemistry, carrier structure, disease biology, and pharmacodynamic biomarkers, to one another. Further investigations are needed to establish intact delivery of the degrader to the target, target depletion in relevant tissues, prolonged pharmacodynamics, favorable safety, and compelling therapeutic benefit relative to free degraders or traditional inhibitors. Thus, it is important to view delivery not simply as an additional step during formulation but as a design principle necessary for the reliable clinical outcome of degradation medicine.
: Exosomes are nanoscale extracellular vesicles (EVs) that mediate intercellular communication by transporting proteins, lipids and nucleic acids. Their biocompatibility, low immunogenicity and intrinsic ability to protect labile cargo make them attractive therapeutic carriers. Yet their clinical translation remains constrained by heterogeneous isolation protocols, variable product purity, inefficient cargo loading, rapid systemic clearance and limited tissue-selective delivery. Engineering strategies, including parental-cell preconditioning, genetic modification, post-isolation cargo loading and surface functionalization, have improved the potency and targeting of exosome-based therapeutics but have not fully solved delivery-related bottlenecks. Microneedle (MN) systems provide a complementary solution by breaching the stratum corneum in a minimally invasive manner and depositing exosomes directly within defined tissue compartments. When integrated with dissolving, hydrogel, cryogenic, core-shell, Janus, threaded or stimulus-responsive MN architectures, exosomes can be retained locally, released in a programmed manner and protected from rapid degradation. This Review first summarizes the biological basis, source-dependent functions and engineering strategies of exosomes, and then outlines the design principles of MN platforms relevant to vesicle delivery. On this basis, we discuss representative studies in which MN systems have been explored to improve the local retention, controlled release and tissue-specific delivery of exosomes in cancer, wound repair, neurological injury, cardiovascular disease, immune-mediated disorders and other regenerative settings. We further summarize the translational barriers that remain for this emerging strategy, including vesicle characterization, potency assays, sterility control, scalable manufacturing, long-term safety, storage stability and batch-to-batch reproducibility.
Yu-Hui Fang, Hao Song, Dong-Xian Li et al.· International Journal of Nan...· 0 citations
Targeted protein degradation (TPD) harnesses endogenous proteolytic machineries—the ubiquitin–proteasome system and lysosomal pathways—to selectively eliminate disease-causing proteins that are refractory to conventional inhibition. In cancer immunotherapy, TPD dismantles critical immunosuppressive nodes across extracellular, membrane and intracellular compartments, reprogramming the tumor microenvironment from an immunologically ‘cold’ to a ‘hot’ state. This Review examines the molecular engineering principles of bifunctional degraders and summarizes clinical progress demonstrating synergy with immune checkpoint blockade and adoptive cell therapy. We discuss how catalytic protein elimination overcomes primary immune evasion and adaptive resistance driven by compensatory signaling, target mutation and metabolic rewiring. Finally, we outline translational roadblocks in cell-specific delivery, therapeutic window optimization and on-target/off-tissue toxicity mitigation, and propose engineering strategies to advance the clinical implementation of targeted protein degradation in immuno-oncology.
Fu-Rong Zhang, Qian-Heng Wang, Ming-Xuan Li et al.· Frontiers in Immunology· 0 citations
This review summarizes recent advances in chemical protein degradation strategies for neurodegenerative disorders and highlights potential future perspectives of multifunctional PROTACs for therapeutic development.
Pasquale Degennaro, Imane Ghafir El Idrissi, Rosa Purgatorio et al.· Pharmaceuticals· 0 citations
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