Engineered Natural Membrane Vesicle Exosomes as a Torin2 Delivery Platform for Targeted Therapy of Anaplastic Thyroid Carcinoma

Anaplastic thyroid carcinoma (ATC) is a highly aggressive malignancy with poor prognosis due to rapid progression and resistance to conventional therapies. Integrin αvβ3 is overexpressed in ATC, making it a promising target. Torin2, a potent mTOR inhibitor, shows antitumor activity but suffers from poor solubility, short half-life, and systemic toxicity. Exosomes offer a natural delivery platform but lack intrinsic tumor tropism. This study aimed to develop iRGD-modified engineered exosomes for targeted delivery of Torin2 to ATC cells.

iRGD-modified exosomes (iRGD-Exos) were generated by transducing HEK-293T cells with a lentiviral vector (EGFP-C1-iRGD-Lamp2b) encoding a fusion protein of enhanced green fluorescent protein (EGFP) and iRGD peptide fused to the N-terminus of lysosomal-associated membrane protein 2b (Lamp2b), a transmembrane protein naturally enriched on exosome surfaces. Torin2 was loaded into iRGD-Exos via electroporation (Torin2@iRGD-Exos). The nanoparticles were characterized for size, morphology, loading efficiency, and stability. Cellular uptake was evaluated in ATC cell lines using flow cytometry and confocal microscopy. In vitro cytotoxicity was assessed by live/dead staining. In vivo antitumor efficacy and biosafety were examined in BHT101 xenograft-bearing nude mice.

iRGD-Exos and Torin2@iRGD-Exos exhibited spherical morphology, appropriate size, and a loading efficiency of 23.68%. iRGD modification significantly enhanced exosome uptake by ATC cells compared to unmodified exosomes. Torin2@iRGD-Exos showed superior in vitro cytotoxicity relative to free Torin2 or Torin2@blank-Exos. In vivo, Torin2@iRGD-Exos markedly suppressed tumor growth without causing significant body weight loss or organ toxicity compared to free Torin2.

The iRGD-modified exosomal delivery system (Torin2@iRGD-Exos) achieves efficient tumor targeting, excellent biocompatibility, and potent antitumor activity against ATC both in vitro and in vivo, offering a promising therapeutic strategy for integrin αvβ3-overexpressing malignancies.

Abstract from PubMed Central (PMID 42948446, PMC13712454). This entry was added automatically by our daily literature monitor because it matches the topics we follow; read the full paper at the original source.