Abstract
<jats:p>Paclitaxel (PTX) serves as the first-line chemotherapeutic agent for castration-resistant prostate cancer (CRPC), yet poor water solubility and severe systemic toxicity severely limit its clinical performance, which cannot be fundamentally addressed by existing intratumoral in situ nanoaggregation strategies. Herein, we synthesized a multi-stimuli-responsive PTX prodrug P1 and constructed an integrated delivery platform P1-EXO using mesenchymal stem cell-derived exosomes (MSC-EXO), which realizes tumor-targeted delivery, intracellular cyclization and self-assembly, as well as hierarchical stimuli-triggered drug release to comprehensively optimize the physicochemical and pharmacokinetic properties of PTX. Experimental results demonstrate that P1-EXO achieves a drug loading efficiency of 44.57% with remarkably enhanced cellular uptake and lysosomal escape; in vivo assays reveal that the combination of P1-EXO and radiotherapy improves tumor growth inhibition by 65.59% and elevates intratumoral drug accumulation by 31.6% relative to free PTX, without evident pathological damage to major organs. This platform integrates the tumor-targeting superiority of exosomes and the long-term retention effect of in situ nanoaggregation, overcoming the clinical limitations of PTX and offering an innovative strategy for precise chemoradiotherapy against CRPC.</jats:p>