Engineered nanovesicle platform simultaneously triggers YAP-dependent ferroptosis and reprograms T-cell immunity...

Area of Science:

• Biotechnology
• Oncology
• Nanomedicine

Background:

• Melanoma is an aggressive cancer with limited treatment options and frequent resistance to immune checkpoint blockade (ICB).
• Extracellular vesicles (EVs) are promising for RNA therapeutics but face challenges in cargo loading and tumor targeting.
• Engineered EVs offer a potential solution to enhance therapeutic delivery and efficacy in melanoma.

Purpose of the Study:

• To develop an engineered EV strategy for efficient miRNA packaging and tumor-specific targeting in melanoma.
• To investigate the therapeutic potential of engineered EVs (iEV-150) in overcoming ICB resistance.
• To elucidate the mechanisms by which iEV-150 exerts anti-tumor effects and modulates the tumor microenvironment.

Main Methods:

• Engineered EVs (iEV-150) were created by co-expressing miR-150-3p and Annexin A2 (ANXA2), with surface modification using iRGD peptides.
• Mechanisms were studied using RNA sequencing, RIP, ChIP, and luciferase assays.
• Ferroptosis induction, therapeutic efficacy, biodistribution, and immune modulation were assessed in melanoma models.

Main Results:

• ANXA2 facilitated selective loading of miR-150-3p into EVs, with iEV-150 showing enhanced melanoma cell uptake and tumor accumulation.
• iEV-150 suppressed NF2, activated YAP signaling, and upregulated ferroptosis genes (ACSL4, CHAC1) via the NF2-Hippo-YAP axis.
• iEV-150 promoted CD8+ T cell infiltration and activation, significantly enhancing ICB efficacy in melanoma models.

Conclusions:

• iEV-150 integrates efficient miRNA loading, tumor targeting, ferroptosis induction, and immune reprogramming.
• This engineered EV platform effectively overcomes ICB resistance in melanoma.
• iEV-150 represents a promising RNA-based therapeutic strategy for precision melanoma treatment.