Extracellular Vesicle-Encapsulated mRNA for Protein Replacement Therapy: A Novel mRNA Delivery Platform Opening Doors for Next-Generation Gene Therapies

Spero Bio is a novel biotechnology company dedicated to researching mRNA-protein therapies loaded into extracellular vesicles. Collaborating researchers have developed a novel messenger RNA (mRNA) delivery system for collagen supplementation therapy in photoaged skin, marking the first pharmacological treatment proven to possess this capability. Recently, Dr. Andrew Lee, founder of Spero Bio, and Dr. Li Li’s team published an article titled “Intradermally delivered mRNA-encapsulating extracellular vesicles for collagen-replacement therapy” in Nature Biomedical Engineering, a subsidiary journal of Nature (Impact Factor: 29.2). The new delivery system applied in the study holds the potential to help mRNA and gene therapies overcome various current obstacles.

After the age of 30, human skin loses approximately 1% of its collagen annually due to the age-related downregulation of relevant gene expression. This age-induced collagen loss is irreversible, leading directly to the formation of wrinkles on the face, hands, neck, and other body parts. In recent years, collagen-based products have been widely applied in the field of anti-aging, giving rise to numerous best-selling items. The efficient delivery and long-term stable expression of collagen are crucial to its efficacy, and related technological breakthroughs hold significant promise for further mitigating the effects of aging.

The article highlights that, to address collagen loss in the skin caused by aging, a research team has pioneered a novel, repeatable-dosing gene therapy platform based on non-viral vector technology. This approach utilizes extracellular vesicles (EVs) to deliver collagen-encoding mRNA into skin cells, where the mRNA is translated into the corresponding protein to exert its therapeutic effect. This cell-derived mRNA therapy enables skin cells to upregulate the expression of native collagen, compensating for collagen depletion resulting from aging or photoaging, and significantly improving age-related symptoms such as wrinkles.

In fact, this “dreamlike” technology is close to reality. SperBio, where Dr. Andrew Lee, Dr. Li Li, and Dr. Ni Jia are based, is refining this gene therapy, with the aim of achieving its first clinical application in patients suffering from collagen loss.

According to reports, Spero Bio is the world’s first company dedicated to developing cell-derived mRNA innovative therapies and related delivery tools. Leveraging independent innovation and collaborations with leading global medical institutions and universities, the company has developed non-synthetic, scalable, and clinically oriented cell-derived mRNA therapies, offering new potential directions for next-generation gene therapy methods. Currently, the company’s innovative R&D pipeline targeting aging-related collagen damage, COL1A1-EV mRNA, has received ethical approval for its first human clinical trial, with dosing of the first cohort of subjects expected to begin in the summer of 2023. Spero Bio is also set to become the first biopharmaceutical company worldwide to test a repeatable-dose, non-viral gene therapy product in humans.

Siper Bio’s “Cell-Derived RNA Therapy” is based on the principle of replacing age-related protein loss in the human body. It delivers mRNA encoding proteins that are downregulated with aging into cells, leveraging the body’s own cellular machinery to compensate for losses caused by aging and photoaging.

This also dictates that mRNA therapeutics must enter the cytoplasm to exert their effects; therefore, the efficient and specific intracellular delivery of mRNA has become the key to therapeutic efficacy.

In response, Sper Bio has innovatively selected extracellular vesicles (EVs) as the “delivery vehicle” for mRNA. As a naturally occurring intercellular messenger system present in all tissues and biological fluids, EVs can selectively release active components such as proteins and nucleic acids to various tissues.

Notably, leveraging its proprietary cell-derived mRNA technology platform, Sibo Bio can directly produce mRNA drugs encapsulated in extracellular vesicles (EVs) from cells. These drug candidates demonstrate enhanced safety profiles, superior lysosomal escape capability, and improved biomembrane permeability. This technology boasts broad applicability across the vast majority of genes, regardless of size. Furthermore, the engineered EVs developed by Sibo Bio exhibit high tissue-specific targeting ability, enabling targeted drug delivery to specific organs and offering a natural, safe, and efficient innovative gene therapy approach.

In contrast, relatively common gene therapies that use viral vectors, primarily adeno-associated virus (AAV), to deliver target genes pose significant risks in terms of immunogenicity, toxicity, and genomic integration. These concerns have led to the failure of many related clinical drug trials in recent years. Furthermore, due to the small packaging capacity of AAV vectors, approximately 80% of human gene sequences cannot be successfully encapsulated, severely limiting their applicability. More challenging still, the presence of anti-AAV neutralizing antibodies triggers an immune response when patients receive subsequent treatments using the same AAV vector, thereby precluding repeat dosing.

In contrast, “cell-derived mRNA therapies” do not utilize viral components, offering inherent advantages in terms of immunogenicity and toxicity. Unlike adeno-associated virus (AAV) vectors, they do not elicit strong immune responses, thereby enabling repeated dosing. Extracellular vesicles can accommodate larger cargo, sufficient to carry nucleic acid sequences with a nucleotide length of up to 14 kb, thus broadening their scope of application.

Compared with the widely used LNP delivery technology, “cell-derived mRNA therapy” employs biologically sourced delivery vehicles, offering advantages in safety and extrahepatic targeting precision over chemically synthesized LNPs. Taking the preclinical trial data released by Sipo Bio as an example, mRNA delivered via EVs elicited milder local reactions, such as inflammation and skin erythema, and demonstrated higher translation efficiency compared to other delivery vectors.

Preclinical study data also indicate that in a photoaging model using nude mice, injection of COL1A1-EV mRNA resulted in a significant increase in collagen expression within the dermis, marked improvement in dorsal wrinkles, and a substantial reduction in wrinkle area. A single regular injection into wrinkled skin can stimulate robust collagen production, with anti-wrinkle effects lasting up to 70 days after a single dose; regular injections every 2–3 months can sustain these benefits for an even longer duration. Notably, this therapy achieves protein replacement by delivering mRNA to enable autologous cells to express native proteins and distribute them throughout the skin. This naturally regulated physiological process avoids risks associated with traditional collagen injections, such as displacement, deformation, and swelling.

The application of cutting-edge technologies in the consumer-grade market has also brought considerable development prospects to Sibo Biotech’s “cell-derived mRNA therapy.”

According to Frost & Sullivan data, the global market size for non-surgical medical aesthetics reached $32 billion in 2021, while in China it approached RMB 100 billion. Among these, the end-user market size for products primarily consisting of botulinum toxin, hyaluronic acid, and collagen accounted for nearly 50% of the non-surgical medical aesthetics market. Allergan, a global giant in medical aesthetics, reported global net revenue (non-end-user) of $2.223 billion for its botulinum toxin product Botox in 2021; for its premium hyaluronic acid product Juvederm, this figure was $1.535 billion. Compared to the highly concentrated botulinum toxin market and the fiercely competitive hyaluronic acid sector, regenerative collagen products are still in their early stages. However, with technological breakthroughs by domestic players in recombinant collagen, the penetration rate of regenerative collagen products has grown rapidly. In this context, Sibo Biotech’s “cell-derived mRNA therapy,” which offers higher safety and superior therapeutic efficacy, is poised to unlock a blue-ocean market worth tens of billions.

The translation and application of cutting-edge technologies rely on teams, funding, and pipelines.

SperBio has assembled a comprehensive team with extensive experience in the development of nanomedicine delivery vectors, cell and gene therapy (CGT) development and collaboration, and the full lifecycle of innovative drug development and industrialization. The company has established a 25-member team responsible for CMC, quality control, clinical sample manufacturing, and clinical research management. Dr. Andrew Lee, Co-founder of SperBio, specializes in the field of cell and gene therapy. He has published over 50 papers and led multiple cell therapy projects from research to clinical stages. Another co-founder, Dr. Li Li, brings over 30 years of experience in nano-engineering and lipid nanoparticle formulation, with more than 400 publications and over 30 patents to his name. Dr. Ni Jia, General Manager of the company, possesses over 14 years of pharmaceutical R&D experience in the industry. He has spearheaded the IND development of more than seven new drugs, including China’s first PROTAC drug, demonstrating proven expertise in leading drugs through the entire process from R&D to market launch.

The promising prospects of its pipeline have also earned Sibo Biotech significant favor from investors. In 2021, the company completed its Series A financing round, co-led by IDG Capital, Shangcheng Capital, and Shanda Investment. Leveraging this funding, Sibo Biotech’s first-phase GMP-compliant manufacturing facility, spanning 2,000 square meters, was constructed and became operational in 2022. According to reports, this GMP-compliant facility can meet the production requirements for Phase I–III clinical trials, positioning Sibo Biotech as the owner of the world’s first cell-derived mRNA gene therapy production line. The company’s clinical development pipeline has subsequently received IRB approval, with first-in-human clinical trials scheduled to commence in 2023.

Sibo Bio is highly confident in the safety and efficacy of COL1A1-EV mRNA and plans to file Investigational New Drug (IND) applications in China, the United States, and Australia, thereby bringing new possibilities to the vast anti-aging market from the perspective of gene therapy.

In fact, the applications of “cell-derived mRNA therapies” are by no means limited to anti-aging. Cell-derived mRNA delivery represents a novel universal approach to gene therapy, with potential functions including the treatment of diseases caused by the deficiency or damage of human proteins. Many rare genetic disorders result from gene/protein deficiencies or insufficient expression. For instance, delivering the corresponding mRNA can facilitate the production of dystrophin, thereby treating Duchenne muscular dystrophy; delivering type VII collagen mRNA can treat rare conditions such as epidermolysis bullosa; and this approach also holds promise for broader applications in oncology.

Sibo Bio will begin with skin, using gene therapy to replace collagen lost due to aging or photoaging, and will subsequently focus on rare diseases as its initial indications and primary therapeutic area. In this process, Sibo Bio also aims to become a leader in next-generation non-viral gene therapy, bringing new possibilities to address more unmet clinical needs.