2026· The Innovation Drug Discovery· Vol 1, pp. 100005· 0 citations· 120 references
TL;DR
The core mechanisms of Nano-TPD, encompassing targeted delivery, intracellular trafficking, stimuli-triggered release, and enhanced protein degradation via UPS or lysosomal pathways, are systematically elaborated.
Abstract
Targeted protein degradation (TPD) has emerged as a transformative therapeutic strategy that overcomes the limitations of conventional small-molecule inhibitors (SMIs) by harnessing the degradation machinery, including the ubiquitin-proteasome system (UPS) and lysosomal pathway. However, traditional TPD agents face substantial challenges in clinical translation, such as poor solubility, low bioavailability, insufficient targeting specificity, and limited tissue penetration. To address these limitations, the integration of nanotechnology has given rise to Nano-TPD as a new generation therapeutic platform that revolutionizes TPD delivery. We first summarize the recent advances in TPD technology for the treatment of common clinical diseases, highlighting key molecular targets and representative degraders. Then, we focus on the design of Nano-TPD platforms, including lipid-based, polymeric, inorganic, and biomimetic nanocarriers, as well as innovative strategies. The core mechanisms of Nano-TPD, encompassing targeted delivery, intracellular trafficking, stimuli-triggered release, and enhanced protein degradation via UPS or lysosomal pathways, are systematically elaborated. Furthermore, we discuss the challenges and future perspectives of Nano-TPD. This review provides a comprehensive overview of Nano-TPD, emphasizing its role in advancing TPD toward clinical utility and expanding its therapeutic scope across various diseases.
Targeted protein degradation (TPD) has redefined the therapeutic landscape by shifting the focus from merely inhibiting protein function to actively eliminating disease-causing proteins. However, the clinical translation of TPD agents remains hampered by their inherent physicochemical limitations, including poor solubility, membrane impermeability, and lack of tissue selectivity. Nanotechnology offers a strategic pathway to overcome these barriers. This review examines the convergence of TPD and nanotechnology, highlighting how diverse nanoplatforms-ranging from lipid and polymeric nanoparticles to inorganic carriers and biomimetic systems-can address fundamental delivery challenges. We discuss key design strategies such as physical encapsulation, chemical conjugation, and carrier-free self-assembly between nanocarrier-assisted TPD-where nanoparticles improve degrader pharmacokinetics-and nanostructure-integrated TPD-where the nanoscaffold directly participates in ternary complex formation, and explore how engineering the nano-bio interface enables precise control over cellular uptake, intracellular trafficking, and ternary complex formation. We also critically assess current translational hurdles, including manufacturing complexity, biosafety concerns, and tumor heterogeneity, while offering perspectives on how rational design and interdisciplinary collaboration can accelerate clinical adoption. By reimagining protein degraders as components of intelligent nano-systems, nano-TPD holds the potential to transform undruggable targets into actionable therapeutic opportunities.
Haoran Zhu, Yijun Zhang, Yu Ning et al.· Small Methods· 0 citations
An overview of the developmental trajectory of the TPD field is provided and how diverse modalities can be leveraged to address intracellular, membrane-associated, and extracellular protein targets are discussed.
Yu-bo Zhang, Junwei Fu, Yue Liu et al.· Acta Pharmacologica Sinica· 0 citations
This thorough analysis investigates the molecular basis of PROTAC technology, tracking its progression from an elegant intellectual notion to a clinically approved treatment platform and provides a detailed survey of the current clinical landscape.
N. Vijaya Lakshmi Reddy, M. Sarika, V. Deepika et al.· International Journal of Adv...· 0 citations
Targeted protein degradation (TPD) has transitioned from a paradigm-shifting concept to a clinically validated strategy, with multiple degraders achieving proof-of-concept in oncology and a rapidly expanding toolbox. By co-opting the ubiquitin-proteasome system to eliminate pathogenic proteins in an event-driven manner, TPD addresses targets long deemed undruggable. To capture this momentum, we present a comprehensive overview of the field. We dissect the mechanisms of heterobifunctional PROTACs and their clinical translation, covering late-stage programs targeting canonical oncogenic drivers (AR, ER, BTK) and emerging first-in-human studies against historically challenging targets such as STAT3 to illustrate both clinical validation and mechanistic expansion. Beyond classical PROTACs, we systematically summarize the expanding TPD toolbox: lysosome-targeting chimeras for degrading extracellular and membrane proteins, autophagy-based degraders for clearing aggregates and damaged organelles, antibody- and nucleic acid-derived PROTAC formats for tissue-specific delivery and transcription factor targeting, deubiquitinase-targeting chimeras for protein stabilization, and proximity-based post-translational modification editing, collectively demonstrating the broad reach of proximity-inducing pharmacology. By integrating molecular mechanisms with therapeutic applications, this review illustrates how TPD is reshaping the druggable proteome. We outline key challenges including novel E3 ligase ligand discovery, tissue selectivity, and acquired resistance, and discuss how covalent fragment screening, artificial intelligence, and expanded E3 ligase repertoires will advance next-generation degraders to fulfill the promise of event-driven pharmacology. This review provides a roadmap for translating TPD into transformative therapies.
Caiyu Wang, Zhibin Guo, Yufei Liu et al.· International journal of pha...· 0 citations
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.
S. Ghosh, R. Banerjee, Hailah M. Almohaimeed et al.· Journal of Cellular and Mole...· 0 citations
INTRODUCTION
Nanoparticle-based drug delivery has emerged as a transformative approach in modern therapeutics, offering improved targeting efficiency, enhanced pharmacokinetics, and reduced systemic toxicity compared to conventional drug delivery systems.
AREAS COVERED
This review comprehensively examines major nanocarrier platforms, including lipid-based, polymeric, inorganic, and hybrid systems, with emphasis on their structural design and functional properties. It further explores current advancements in targeting strategies, including passive targeting via the enhanced permeability and retention (EPR) effect and active targeting through ligand-receptor interactions involving antibodies, peptides, aptamers, and small molecules. Key biological and technological barriers to clinical translation are also discussed, such as tumor heterogeneity, abnormal vasculature, dense extracellular matrix, immune clearance, and limited cellular uptake. Additionally, emerging stimuli-responsive systems, including pH-, redox-, and enzyme-sensitive nanocarriers, are highlighted for their role in controlled and site-specific drug release.
EXPERT OPINION/COMMENTARY
Despite significant progress, the clinical translation of nanomedicine remains constrained by biological complexities and scalability challenges. Future advancements integrating biomimetic strategies, multifunctional design, and artificial intelligence-driven modeling are expected to enhance targeting precision, biocompatibility, and translational success.
Nithya Ajay, Anu Shibi Anilkumar, R. Veerabathiran· Therapeutic delivery· 0 citations
