In situ self-assembly of PROTACs for precision cancer therapy.

PROTAC-Based Strategies in Neurodegenerative Diseases: Challenges and Perspectives

This review summarizes recent advances in chemical protein degradation strategies for neurodegenerative disorders and highlights potential future perspectives of multifunctional PROTACs for therapeutic development.

Exosome‐Mediated Delivery of PROTACs for Targeted Protein Degradation in Cancer, Neurodegenerative, Infectious, and Inflammatory Diseases

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.

Targeted protein degradation dismantles undruggable targets to reverse immune evasion and therapy resistance in cancer

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.

BioPROTACs: a promising approach for targeted protein degradation.

TARGETED PROTEIN DEGRADATION WITH PROTACS IN CANCER THERAPY: MECHANISMS, CLINICAL ADVANCES, CHALLENGES, AND FUTURE PERSPECTIVES

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.

Drug-likeness defects drive carrier-free cyanine-PROTAC self-assembly for tumor-specific protein degradation.

Proteolysis-targeting chimeras (PROTACs) offer a powerful strategy for targeted protein degradation but suffer from poor solubility, bioavailability, and in vivo distribution due to their "beyond rule-of-five" physicochemical properties, severely limiting clinical translation. Here, we transform these intrinsic drug-likeness liabilities into a driving force for molecular self-assembly by developing a carrier-free nanoplatform in which PROTACs spontaneously co-assemble with cyanine dyes, including IR783 and the clinically approved indocyanine green (ICG). This strategy generates stable supramolecular assemblies with ultra-high PROTAC loading (up to 70 wt%) without the need for exogenous carriers, while imparting intrinsic NIR fluorescence for real-time, non-invasive in vivo tracking. The assemblies undergo stimuli-responsive disassembly upon ultrasound or X-ray irradiation, enabling spatiotemporally controlled PROTAC release within tumors. Incorporation of diselenide-bridged cyanine derivatives further confers radiosensitization capability, allowing synergistic combination with radiotherapy. In vivo studies demonstrate efficient tumor accumulation, robust target protein degradation, and potent antitumor efficacy. Collectively, this work establishes a versatile supramolecular strategy that directly addresses the long-standing delivery challenges of PROTACs and advances precise, controllable oncological therapy.