Self-assembling heterodimeric prodrug nanoparticles for dual-targeted cancer therapy via the disruption of redox homeostasis and Pin1 degradation.

Disrupting redox balance by elevating reactive oxygen species (ROS) selectively induces cancer cell death while sparing healthy tissues. Peptidyl-prolyl isomerase (Pin1) is overexpressed in several cancer cells and plays a critical role in tumorigenesis and tumor progression. All-trans retinoic acid (RA) is known to induce cell death by generating ROS and directly binding the active site of Pin1, leading to cancer cell death. In this work, we developed boronated RA-based heterodimeric prodrug (BRDP) to fully enhance RA's functions as both a redox homeostasis disruptor and a Pin1 inhibitor for dual targeted cancer therapy. BRDP self-assembled into colloidal nanoparticles in the presence of sulfated polysaccharide fucoidan, which binds P-selectin overexpressed on cancer cells. Fucoidan-modified boronated BRDP (f-BRDP) nanoparticles amplified oxidative stress by simultaneously generating ROS and depleting glutathione (GSH), leading to enhanced cancer cell death. Additionally, f-BRDP degraded Pin1, activating tumor suppressors and inactivating oncogenes. In vivo xenograft studies confirmed that f-BRDP nanoparticles preferentially accumulated at tumor sites and significantly inhibited tumor growth with minimal systemic toxicity. These findings highlight f-BRDP nanoparticles as a promising tumor-targeted therapeutic platform that overcomes the limitations of conventional therapeutics and advances precision nanomedicine. We believe that f-BRDP nanoparticles offer a novel approach to expanding the clinical applications of RA in targeted cancer therapy while addressing the limitations of carriers-mediated drug delivery.