Nano-polymeric platinum activates PAR2 gene editing to suppress tumor metastasis

Area of Science:

• Oncology
• Nanotechnology
• Gene Editing

Background:

• Cancer metastasis is a major cause of mortality, often exacerbated by chemotherapy.
• Protease-activated receptor 2 (PAR2) plays a key role in promoting cancer cell migration and metastasis.
• CRISPR/Cas9 gene editing offers a potential strategy to inhibit metastasis, but effective delivery remains a challenge.

Purpose of the Study:

• To develop a nanoparticle-based delivery system for CRISPR/Cas9 to target PAR2 and inhibit cancer metastasis.
• To evaluate the efficacy of this system in reducing metastasis and chemotherapy-induced toxicity both in vitro and in vivo.

Main Methods:

• Nanosized polymeric platinum (NanoPt) was utilized as a drug carrier for CRISPR/Cas9.
• The NanoPt@Cas9-PAR2 system was designed to deliver CRISPR/Cas9 for PAR2 gene editing.
• In vitro and in vivo studies were conducted to assess anti-metastatic effects and toxicity.

Main Results:

• NanoPt@Cas9-PAR2 significantly enhanced anti-metastatic effects compared to conventional treatments.
• The system effectively alleviated the systemic toxicity associated with platinum-based chemotherapy.
• PAR2 deficiency induced by NanoPt@Cas9-PAR2 attenuated epithelial-mesenchymal transition (EMT) and ferroptosis via RAGE/ERK signaling, inhibiting cancer cell migration.

Conclusions:

• NanoPt@Cas9-PAR2 represents a safe and effective all-in-one combinatorial strategy for cancer treatment.
• This approach mitigates PAR2 signaling and reduces platinum cytotoxicity, offering a promising therapeutic avenue.
• Targeting PAR2 with CRISPR/Cas9 delivered via nanoparticles shows potential for overcoming metastasis and therapy resistance.