The Mechanistic Review of the Molecular Interface of RNA-Loaded Extracellular Vesicles: Redefining Targeted Therapy for Autoimmune Disorders

Orassay, Aliya; Yerzhigit, Naizabek; Ganina, Anastassiya; Chuvakova, Elmira; Lookin, Oleg; Baigenzhin, Abay

doi:10.3390/ijms27104323

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The Mechanistic Review of the Molecular Interface of RNA-Loaded Extracellular Vesicles: Redefining Targeted Therapy for Autoimmune Disorders

by

Aliya Orassay

^*,

Naizabek Yerzhigit

,

Anastassiya Ganina

,

Elmira Chuvakova

^*,

Oleg Lookin

and

Abay Baigenzhin

JSC National Scientific Medical Center, 42 Abylay Khan Ave., Astana 010009, Kazakhstan

^*

Authors to whom correspondence should be addressed.

Int. J. Mol. Sci. 2026, 27(10), 4323; https://doi.org/10.3390/ijms27104323

Submission received: 13 March 2026 / Revised: 12 April 2026 / Accepted: 30 April 2026 / Published: 12 May 2026

(This article belongs to the Section Molecular Immunology)

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Abstract

Traditional treatments of autoimmune diseases relying on systemic immunosuppression often lack curative potential and have severe side effects. Mesenchymal stem cells (MSCs) are a promising alternative due to their immunomodulatory properties; however, whole-cell therapies have certain limitations. MSC-derived extracellular vesicles (EVs), including small vesicles—exosomes—have emerged as a safe cell-free therapeutic platform capable of crossing biological barriers and delivering bioactive cargo with low immunogenicity. Various types of RNAs abundantly produced by host MSCs represent a key element of EV content. In particular, EVs carry small RNAs, which essentially determine cellular life and fate. Our review provides a comprehensive mechanistic framework for the use of RNA-loaded EVs, specifically those carrying microRNAs (miRNAs), small interfering RNAs (siRNAs), and messenger RNAs (mRNAs), in restoring immune homeostasis. We detail the biogenesis and molecular mechanisms governing sorting of RNA into EVs, along with endogenous and exogenous engineering strategies to enhance therapeutic potency. We examine how RNA-loaded EVs modulate immunological processes like reprogramming of macrophage M1-M2 polarization, Th17/Treg balance, and suppression of inflammatory signaling pathways such as NF-κB and the NLRP3 inflammasome. We address critical translational challenges—EV heterogeneity, manufacturing scalability, and need for standardized quality control—while outlining future opportunities for RNA-loaded EV-based therapeutics.

Keywords: autoimmune diseases; extracellular vesicles; mesenchymal stem cells; miRNA; siRNA; RNA therapeutics; immunomodulation

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MDPI and ACS Style

Orassay, A.; Yerzhigit, N.; Ganina, A.; Chuvakova, E.; Lookin, O.; Baigenzhin, A. The Mechanistic Review of the Molecular Interface of RNA-Loaded Extracellular Vesicles: Redefining Targeted Therapy for Autoimmune Disorders. Int. J. Mol. Sci. 2026, 27, 4323. https://doi.org/10.3390/ijms27104323

AMA Style

Orassay A, Yerzhigit N, Ganina A, Chuvakova E, Lookin O, Baigenzhin A. The Mechanistic Review of the Molecular Interface of RNA-Loaded Extracellular Vesicles: Redefining Targeted Therapy for Autoimmune Disorders. International Journal of Molecular Sciences. 2026; 27(10):4323. https://doi.org/10.3390/ijms27104323

Chicago/Turabian Style

Orassay, Aliya, Naizabek Yerzhigit, Anastassiya Ganina, Elmira Chuvakova, Oleg Lookin, and Abay Baigenzhin. 2026. "The Mechanistic Review of the Molecular Interface of RNA-Loaded Extracellular Vesicles: Redefining Targeted Therapy for Autoimmune Disorders" International Journal of Molecular Sciences 27, no. 10: 4323. https://doi.org/10.3390/ijms27104323

APA Style

Orassay, A., Yerzhigit, N., Ganina, A., Chuvakova, E., Lookin, O., & Baigenzhin, A. (2026). The Mechanistic Review of the Molecular Interface of RNA-Loaded Extracellular Vesicles: Redefining Targeted Therapy for Autoimmune Disorders. International Journal of Molecular Sciences, 27(10), 4323. https://doi.org/10.3390/ijms27104323

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The Mechanistic Review of the Molecular Interface of RNA-Loaded Extracellular Vesicles: Redefining Targeted Therapy for Autoimmune Disorders

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