Synthesis of RARα-PROTAC and its delivery via Polygonatum sibiricum exosome-like nanoparticles for the treatment of colorectal cancer.

Retinoic acid receptor α (RARα) is a promising yet challenging target in treating colorectal cancer (CRC). Traditional RARα-binding modulators often fail to fully inhibit downstream oncogenic pathways and cannot eliminate the pre-existing RARα protein, frequently resulting in drug resistance and treatment failure. To overcome these limitations, we designed a series of proteolysis-targeting chimeras (PROTACs) based on the ligand CA77.1, which are bifunctional molecules that recruit the ubiquitin-proteasome system for RARα degradation.​Among these candidates, compound Z1 proved the most potent degrader, demonstrating a DC50 of 6.02 ± 1.05 μM and effective suppression of CRC cell proliferation and migration. Considering the generally poor solubility and membrane permeability of PROTACs, we encapsulated Z1 within Polygonatum sibiricum exosome-like nanoparticles (PsELNs). Compared with free Z1, the Z1/PsELNs delivery system enhanced RARα degradation in vitro by 2.2-fold and improved in vivo antitumor efficacy by 1.8-fold, while also promoting tumor targeting and overall bioavailability. These findings provide a feasible strategy for degrading RARα in CRC and highlight the potential of plant-derived exosome-like nanoparticles as efficient carriers for PROTAC delivery, indicating a new direction for targeted cancer therapy.