Self-Assembled Nano-PROTAC to Improve Targeted Therapy in Castration-Resistant Prostate Cancer

A new study published in Nature Signal Transduction and Targeted Therapy reports a major leap in the design of targeted cancer therapies through the development of an in vivo self-assembled nano-PROTAC (proteolysis targeting chimera) system capable of delivering dual-targeted degradation in castration-resistant prostate cancer (CRPC).​
PROTACs have reshaped the drug discovery landscape by inducing selective degradation of disease-associated proteins via the ubiquitin–proteasome system. However, their clinical potential has been hindered by three core challenges: poor membrane permeability, suboptimal pharmacokinetics, and the “hook effect” that undermines degradation efficiency at higher doses.​

The newly developed nano-PROTAC addresses these barriers through a self-assembly mechanism that forms stable nanostructures in physiological conditions. This innovation enhances circulation stability, controlled release, and tumor penetration, transforming a molecular degrader into a precise nanotherapeutic platform.

One of the most remarkable aspects of this research is the dual-targeting strategy. The nano-PROTAC simultaneously degrades two proteins essential for CRPC survival and proliferation, amplifying antitumor efficacy beyond what single-target approaches can achieve. This dual action promotes proteolytic synergy and minimizes compensatory signaling that commonly drives resistance.​

In animal models of advanced prostate cancer, the nano-PROTAC demonstrated significant tumor growth inhibition with minimal systemic toxicity, highlighting its biocompatibility and therapeutic precision. By assembling intracellularly, the nanostructures ensure selective degradation within malignant tissues, sparing healthy cells from off-target degradation.​

The study further demonstrates spatiotemporal control of PROTAC release, allowing degradation to occur only within the tumor microenvironment. This localized activation addresses a critical issue in conventional therapies—the systemic off-target degradation of essential proteins that often leads to dose-limiting toxicity.

The implications of this work are profound. Self-assembled nano-PROTAC systems may bridge the gap between molecular degraders and physiological delivery systems, ushering in a new therapeutic era for treatment-resistant malignancies. In particular, these findings open avenues for applying similar nanoplatforms to other refractory cancers where molecular degraders alone have failed due to bioavailability and targeting constraints.​

Looking forward, optimization of ligand selection, payload composition, and biodegradability will be central to advancing nano-PROTACs toward human clinical trials. Additionally, pairing such systems with immune checkpoint inhibitors or radioligand therapy could potentiate synergistic effects in advanced prostate cancer.

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