Apoptosis‐Amplified Intracellular Paclitaxel Nanoparticle Formation Enhances Microtubule Aggregation and PANoptosis
Abstract
Abstract 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.
Article Details
Authors (17)
Xiaoyang Liu
Department of Chemical and Biological Engineering
Xianbao Sun
State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering
Yu Ma
Qiaochu Jiang
State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering
Yun Yin
Hai‐Dong Xu
State Key Laboratory of Digital Medical Engineering School of Biological Science and Medical Engineering Southeast University Nanjing China
Xiaotong Cheng
State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering
Yang Yang
Yinghuan Li
Key Laboratory of Luminescence Analysis and Molecular Sensing, Ministry of Education, College of Chemistry and Chemical Engineering Southwest University Chongqing 400715 China
Hongzhe Yan
State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering Southeast University 2 Southeast University Road Nanjing 211189 China
Xinping Zhang
Xinwang Yu
State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering Southeast University 2 Southeast University Road Nanjing 211189 China
Wenjun Zhan
State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering
Fu‐Gen Wu
State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering Southeast University 2 Southeast University Road Nanjing 211189 China
Xiaofeng Wu
Materials Innovation Factory, Department of Chemistry
Ying Zhuo
Gaolin Liang
State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering