TAT/TK nanomicelles delivering celastrol suppress lung cancer growth and metastasis via NLRP3-driven pyroptosis

Current therapeutic modalities for lung cancer and its pulmonary metastases offer only limited suppression, leading to poor patient prognosis. This critical gap necessitates the development of safe, low-toxicity drug-delivery systems that combine robust tumor targeting with potent suppression of tumor growth and effective blockade of metastasis. Celastrol, a natural compound, possesses known anti-cancer properties, but its systemic delivery and targeting to the tumor microenvironment remain challenging. This study explores a novel nanomicelle system to overcome these limitations, focusing on enhancing delivery and leveraging NLRP3-mediated pyroptosis as a therapeutic mechanism.

Researchers engineered TAT/TK dual-modified nanomicelles loaded with celastrol (Cel). The micelle system incorporates the cell-penetrating peptide YGRKKRRQRRR (TAT) for efficient tumor-specific accumulation and cellular uptake, and a thioketal (TK) linker for reactive oxygen species (ROS)-responsive site-specific drug release within the tumor microenvironment. Comprehensive experiments were conducted both in vitro (cell proliferation, apoptosis) and in vivo (tumor growth, metastasis, pyroptosis factor expression) to evaluate the preparation's tumor-targeting, inhibitory capabilities, and mechanistic effects.

The TAT/TK-Cel nanomicelles demonstrated excellent tumor-targeting and inhibitory capabilities, effectively delivering celastrol to cancerous tissues.

Both in vitro and in vivo results showed that the nanomicelles significantly inhibited tumor cell proliferation and promoted apoptosis. Furthermore, the system effectively suppressed tumor cell metastasis, a critical challenge in lung cancer treatment. Mechanistically, the TAT/TK-Cel nanomicelles regulated the expression of pyroptosis-related factors and activated NLRP3-related pathways within the tumor microenvironment. This NLRP3-driven pyroptosis, a form of programmed cell death, contributes to the observed anti-tumor effects, suggesting a novel pathway for therapeutic intervention beyond traditional apoptosis.