Recently, the latest research findings achieved by Prof. Liang Gaolin’s research team from the School of Biological Science and Medical Engineering, at SEU and the 

National Key Laboratory of Digital Medical Engineering, were published in Angewandte Chemie-International Edition, an internationally renowned academic journal. The 

paper, titled “Apoptosis-Amplified Intracellular Paclitaxel Nanoparticle Formation Enhances Microtubule Aggregation and PANoptosis,” proposes a novel strategy of cancer 

treatment. This strategy enhances the concept of “apoptosis-amplified intracellular paclitaxel nanoparticle formation,” which enhances microtubule aggregation in cancer 

cells, efficiently triggering pan-apoptosis (PANoptosis) and demonstrating excellent therapeutic effects in an animal model of orthotopic breast cancer. This provides a new 

perspective for the precise treatment of breast cancer.

Paclitaxel, a first-line small-molecule chemotherapeutic drug, has long been a subject of research focused on enhancing its efficacy while reducing side effects. Existing 

optimization methods, such as increasing the dosage, may cause systemic toxicity. In contrast, traditional paclitaxel nanoformulations can increase the concentration of the 

drug but are still limited by the extremely low uptake efficiency of cancer cells (with most intracellular nanoparticle delivery efficiencies being less than 0.7%). Previously, 

Liang Gaolin's team successfully utilized CBT-Cys reactions to assemble paclitaxel nanoparticles in situ within cancer cells, thereby overcoming multidrug resistance in 

tumors and achieving excellent anti-tumor effects. This demonstrated that the formation of intracellular paclitaxel nanoparticles is an efficient strategy for tumor treatment.

Building upon paclitaxel’s core mechanism of action, which stabilizes microtubules, blocks cell division, and induces apoptosis in cancer cells, and the specificity of 

caspase-3, a key executioner of apoptosis, in cleaving the DEVD peptide sequence, this research further proposes an innovative hypothesis: By utilizing the caspase-3 

induced by paclitaxel to specifically cleave the DEVD peptide, the efficiency of paclitaxel nanoparticle formation inside cancer cells can be amplified, thereby further 

enhancing the anti-tumor effect of paclitaxel.

Based on this concept, the team designed a paclitaxel prodrug, AcDEVDC(StBu)K(PTX)CBT, which includes three key components (as shown in Fig. a): the AcDEVD 

peptide sequence (a caspase-3-specific substrate), the stert-butyl mercaptan (StBu)-protected cysteine (Cys), and the 2-cyano-benzothiazole (CBT) structure (used for 

CBT-Cys click reactions), as well as the paclitaxel therapeutic unit. The mechanism of action of this prodrug inside cancer cells is illustrated in 

Fig. b: Ac-DEVDC(StBu)K(PTX)-CBT undergoes reduction by glutathione (GSH) and cleavage by caspase-3, triggering the CBT-Cys click reaction and self-assembling into

paclitaxel nanoparticles. These nanoparticles not only aggregate microtubules and promote cancer cell apoptosis but also activate more caspase-3, driving further 

nanoparticle formation and creating a “therapeutic amplification loop.” In vitro experiments demonstrated that this compound significantly inhibits cell cycle progression, 

downregulates the phosphorylated YAP-1 protein level by approximately 48%, and successfully induces PANoptosis via the ZBP-1/AIM2 pathway. In an orthotopic tumor 

model, compared to free paclitaxel treatment, Ac-DEVDC(StBu)K(PTX)-CBT significantly upregulated caspase-3 expression in tumor tissues and effectively prolonged the 

survival time of model animals by disrupting the cytoskeletal structure. This innovative therapeutic strategy provides a novel approach for efficient clinical tumor treatment.

The first author of the paper is Liu Xiaoyang, a “Zhishan” researcher at SEU. Prof. Liang Gaolin, Chief Professor at SEU and Deputy Director of the National Key Laboratory of 

Digital Medical Engineering, is the corresponding author. This research was supported by the National Key Research and Development Program, the National Natural Science 

Foundation, the Jiangsu Province Double Innovation Team, the Jiangsu Provincial Natural Science Foundation, the National Postdoctoral Program, the Jiangsu Province 

Excellent Postdoctoral Program, and the China Postdoctoral Science Foundation.

The paper’s link:

https://onlinelibrary.wiley.com/doi/10.1002/anie.202517035