A novel delivery system for extracellular vesicle-loaded mRNA provides new directions for next-gener

The skin can be smooth and firm because collagen in the skin supports it, accounting for 70% of the skin's dry weight. However, as time passes and youth fades, the amount of collagen in human skin diminishes year by year, and the skin progressively loses strength and wrinkles form. Various medical aesthetic treatments are developed to restore depleted collagen. However, due to the limitations of limited bioavailability of big molecules of collagen, difficulties in entering the epidermis, not easily absorbed by the dermis, and poor transport stability, most of the benefits are not long-lasting and natural.

Recently, a collaborative study by Prof. Andrew Lee's team at Peking University Shenzhen Research Institute/Shenzhen Bay Laboratory, Prof. Betty Y.S. Kim's team at The University of Texas M.D. Anderson Cancer Center, and Prof. Lan Feng's team at Fu Wai Hospital, Chinese Academy of Medical Sciences found that EVs-based intradermal delivery of the COL1A1 gene may provide an effective protein for the treatment of photoaging skin alternative therapy.

The study was based on a mouse model of acute photoaging in which extracellular vesicles (EVs) produced by modified human skin fibroblasts were loaded with extracellular matrix COL1A1-type collagen mRNA for delivery to recipient skin cells. The utility of exosome-based COL1A1 mRNA treatment to replace dermal collagen loss as an anti-aging treatment for photoaging skin was demonstrated.

To improve the efficiency of mRNA delivery and retention, researchers delivered collagen mRNA uniformly and efficiently to the dermis via a hyaluronic acid (HA) microneedle (COL1A1-EV MN) patch, resulting in sustained and stable collagen expression and improved treatment of photoaging skin wrinkles. The study, published in Nature Biomedical Engineering, is entitled "Intradermally delivered mRNA-encapsulating extracellular vesicles for collagen-replacement therapy".

Exosomes and microvesicles, for example, serve critical roles in the transfer of chemicals and nucleic acids (including mRNA) in the human body. As a result of their innate biocompatibility, capacity to penetrate physiological barriers, and minimal immunogenicity, EVs have emerged as possible carriers for nucleic acid treatment in recent years. However, most research concentrating on nucleic acid transport has focused on tiny molecules in the 10–20 nt range, such as microRNAs and small interfering RNAs (siRNAs), while bigger nucleic acids, such as mRNAs, have seldom been assessed due to the difficulties of loading into EVs.

With the introduction of two novel mRNA COVID-19 vaccines, mRNA therapeutics have been able to advance quickly. However, the success of mRNA therapeutics is strongly reliant on the availability of delivery mechanisms capable of converting genetic information into functional proteins in a safe, effective, and stable manner. Current techniques for mRNA delivery center on the encapsulation and transport of lipid nanoparticle (LNP) carriers. However, there are drawbacks to LNP delivery, such as cytotoxicity, poor biodistribution, lack of targeting, and immunogenicity. As a result, the development of a new generation of mRNA delivery methods capable of overcoming the drawbacks of LNP delivery will help to advance mRNA therapeutics.

Cellular nanoporation (CNP) is an mRNA loading technology created by researchers that enables for large-scale generation of EVs with intact endogenous mRNAs and usage in nucleic acid therapy. EVs loaded with mRNA can be employed for protein replacement therapy in a dermal collagen photodepletion model. CNP was also shown to be capable of loading large copy number COL1A1 mRNA (~4000 + nt) into EVs, which earlier post-insertion loading techniques could not do. In vivo studies revealed that COL1A1-EV could restore COL1A1 protein expression in the skin of a mouse model of acute photoaging.

Furthermore, the researchers investigated the changes in COL1A1 mRNA and protein in vivo over time and discovered that the matching protein was translated as early as 12 hours after delivery, peaking at day 4, and continuing for several weeks. To improve the method's suitability for long-term protein replenishment, the author developed a microneedle array for COL1A1-EV administration, which allows for more uniform distribution of EV loaded with mRNA into local skin tissues while reducing membrane breakage.

Only mRNA is delivered via the microneedle system in the article, but the system is equally suitable for packaging other types of EV carriers like miRNA, siRNA, and other bioactive therapeutics such as peptides and proteins.