Engineered Extracellular Vesicles for Targeted Delivery of Therapeutic RNA Nanoparticles to Melanoma Cells

• Grant number: 24/09411-8
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: September 10, 2024
• End date: August 17, 2025
• Field of knowledge: Physical Sciences and Mathematics - Chemistry
• Principal Investigator: Luciana Nogueira de Sousa Andrade
• Grantee: Nathalia Leal Santos
• Supervisor: Kirill Afonin
• Host Institution: Instituto do Câncer do Estado de São Paulo Octavio Frias de Oliveira (ICESP). São Paulo , SP, Brazil
• Institution abroad: University of North Carolina at Charlotte (UNCC), United States
• Associated to the scholarship: 21/13681-2 - Modulation of immune infiltration profile and radiotherapy response in melanomas by miR-195-enriched extracellular vesicles, BP.DR

Abstract

Melanoma poses a significant challenge due to its aggressive nature and resistance to standard-of-care approaches. RNA-based drugs, targeting multiple key pathways, have been investigated as an alternative to bypass these resistant phenotypes and enhance treatment efficacy. Despite the recent advances, RNA chemical instability, rapid clearance, and lack of specific tumor targeting still represent important challenges for translational medicine. In this scenario, the use of lipid-based nanoparticles, such as extracellular vesicles (EVs), as drug RNA-based delivery systems, has emerged as a promising approach. We are currently investigating the potential of tumor-derived EVs enriched with the tumor suppressor miRNA, miR-195-5p, in regulating melanoma growth, immune response and fractionated radiotherapy (RT) efficacy in a 3D spheroid model. Although miR-195 EVs impairs spheroid growth and improves short-term RT response, their therapeutic potential seems to be limited by low penetration capacity within spheroids. Additionally, spheroid outgrowth post RT/EV treatment indicates a scape mechanism possibly associated with expression of resistance-related genes. Dr Kirill Afonin´s research group has been developmenting Rnucleic acid nanoparticles, NANPs, for the controlled and synchronized delivery of multiple small interfering RNAs (siRNAs) as a novel combinatorial RNAi therapeutic approach. Based on this, we aim to (1) develop NANPs for the delivery of miR-195-5p along with siRNAs targeting treatment-induced gene signatures associated with RT resistance, and (2) load them into peptide-functionalized EVs and EV-mimetic nanoparticles for the specific and efficient delivery of these therapeutic RNAs to melanoma cells.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

ASSUNCAO, RAPHAELA REBECA SILVEIRA; SANTOS, NATHALIA LEAL; ANDRADE, LUCIANA NOGUEIRA DE SOUSA. Extracellular vesicles as cancer biomarkers and drug delivery strategies in clinical settings: Advances, perspectives, and challenges. Clinics, v. 80, p. 8-pg., 2025-05-01. (24/09411-8, 23/16355-4)

REBOLLEDO, LAURA P.; SANTOS, NATHALIA LEAL; AFONIN, KIRILL A.. A modular platform for nucleic acid-driven multimerization of nanobodies for advanced molecular imaging. MOLECULAR THERAPY-NUCLEIC ACIDS, v. 35, n. 4, p. 2-pg., 2024-12-10. (24/09411-8)