アポトーシス増強型細胞内パクリタキセルナノ粒子形成は、微小管凝集とPANoptosisを増強する

The clinical efficacy of paclitaxel is limited by systemic toxicity at high doses and poor cellular uptake of nanoformulations. Intracellular paclitaxel nanostructure formation is a promising strategy, yet further enhancing its anticancer effect remains challenging. Herein, we propose a strategy of intracellular apoptosis-amplified paclitaxel nanoparticle formation by rationally designing a caspase-3-responsive peptide-paclitaxel conjugate Ac-Asp-Glu-Val-Asp-Cys(StBu)-Lys(paclitaxel)-CBT (Ac-DEVDC(StBu)K(PTX)-CBT). Upon intracellular glutathione reduction and caspase-3 cleavage, Ac-DEVDC(StBu)K(PTX)-CBT undergoes a CBT-Cys click reaction and subsequent self-assembly into paclitaxel nanoparticles. These nanoparticles aggregate microtubules and promote apoptosis, thereby activating more caspase-3 to drive further nanoparticle formation, creating an amplification loop for enhancing therapeutic outcome. In vitro, Ac-DEVDC(StBu)K(PTX)-CBT remarkably inhibited cell cycle, downregulated phosphorylated YAP-1 level by ∼48%, and induced ZBP-1/AIM2-based PANoptosis. Furthermore, in orthotopic tumor models, Ac-DEVDC(StBu)K(PTX)-CBT significantly increased caspase-3 expression compared to free paclitaxel treatment and markedly prolonged survival via cytoskeleton disruption. This strategy holds high promise for enhanced tumor treatment in the clinic.