HealiRNA Biotech: Can Its Non-LNP CLS Delivery Platform Enable a Breakthrough in the mRNA Race?
mRNA is a type of single-stranded RNA transcribed from one strand of DNA as a template, carrying genetic information and directing protein synthesis. Theoretically, mRNA can express any protein and is also known as the “master key,” enabling the exploration of treatments for nearly all protein-based diseases. In the development of COVID-19 vaccines, mRNA technology underwent its first industrial-scale validation and accelerated its commercialization process.
As the mRNA vaccine development pipeline becomes increasingly robust, its manufacturing processes are gradually maturing. Based on the technical principles of mRNA, its development primarily faces challenges in two areas: how to utilizeSynthetic ModificationTechnological solutions to address the low stability and susceptibility to degradation of mRNA molecules, as well as the development ofDelivery Technologyto enhance the efficiency of molecular entry into human cells while simultaneously generating antigens to stimulate an immune response in the body.
“Current mainstream LNP delivery technologies have certain limitations, and are also constrained by stringent patent barriers,” said Zhao Lixiang, Co-founder and Chief Technology Officer of Huiyi Biomedical. In 2021, three scientists with extensive experience in the field of nucleic acid therapeutics—Zhong Tianyi, Jiang Jianhao, and Zhao Lixiang—quickly reached a consensus based on their respective insights into technology and industry: to establish a hard-tech company that achieves breakthroughs in the core underlying technologies of nucleic acid therapeutics, addressing the most critical pain points hindering the development of China’s nucleic acid drug industry.
Four months after its establishment, Huiyi Biomedical secured angel-round financing from Sequoia China, Jinpu Health, and Huiding Investment. In February this year, the company closed a Pre-A round of over RMB 100 million, with participation from Juming Venture Capital, Shunwei Capital, Zhongxin Capital, and Yajie Fund, while existing investor Sequoia China continued to increase its stake.
Within just two years of its establishment, Huiyi Biomedical has completed two rounds of financing amounting to hundreds of millions of yuan and has garnered sustained attention from Sequoia China. In the highly competitive field of nucleic acid therapeutics, what has enabled Huiyi Biomedical to stand out?
Unlike other drugs, RNA molecules must enter cells to exert their therapeutic effects. However, RNA molecules are negatively charged and susceptible to nucleases widely present in the body. Therefore, the primary challenge in the development and application of RNA-based therapeutics lies in drug delivery technology. In RNA drug research and development, the importance of delivery technology accounts for more than 70%.
Currently, the mainstream approach for delivery systems is the use of LNP (lipid nanoparticle) delivery technology. This technology is primarily controlled by the Canadian company Arbutus, which has filed multiple targeted protective patents. Consequently, it is extremely difficult for other drug development companies to design around these patents.
According to annual reports from major pharmaceutical companies, the world’s top-selling drug is Pfizer’s mRNA vaccine, which utilizes lipid nanoparticle (LNP) delivery technology. Among the three leading players in mRNA technology, BioNTech and CureVac have both opted to license Arbutus’s patented technologies, whereas Moderna has pursued independent in-house development. The LNP delivery technology space has been marked by numerous patent lawsuits among pharmaceutical companies; ultimately, even Moderna, with over a decade of experience in developing delivery technologies, has not been able to avoid patent disputes.
As the first-generation delivery technology, lipid nanoparticles (LNPs) have had their efficacy and safety thoroughly validated; however, the technology is not yet "impeccable." Significant hepatic accumulation can lead to local hypersensitivity reactions and a high likelihood of liver injury. Meanwhile, issues such as susceptibility to oxidative degradation and poor batch-to-batch reproducibility in manufacturing remain to be resolved.
“Despite the large-scale application of LNPs, there is still room for technological improvement, and patent issues cannot be avoided.“Therefore, we chose to start with delivery technology and develop mRNA drugs based on a route completely different from existing LNPs,” said Zhao Lixiang. Based on this starting point, Huiyi Biomedical is pioneering an unproven direction at the forefront of global research—a CLS (cell-like membrane) delivery system with proteins as its main component. This system is regarded by the industry as the second-generation nucleic acid drug delivery technology following LNP delivery technology.
Huiyi Biologics’ independently innovated CLS delivery system is designed based on the protein-phospholipid layer of biomimetic cell membranes, featuring high affinity and release efficiency, and is suitable for various gene therapies including mRNA, siRNA, and CRISPR.CLS is primarily protein-based, offering high safety and fewer side effects. By modifying the types of protein-like components, it can enhance tissue and organ targeting.Currently, in Huiyi Biomedical’s spleen-targeted formulation (CLS-spleen), both targeting efficiency and expression levels are 50-fold higher than those of conventional LNPs; in the therapeutic tumor vaccine vector (CLS-tumor), it elicits CD8+ T cell responses that are 6-fold greater than LNP-SM-102 and 3-fold greater than LNP-ALC-0315.
Based on the new-generation delivery technology CLS, Huiyi Biomedical has also constructedIntelligent RNA Sequence Design Library and IVT Synthesis Platform、Microfluidic Nanomedicine Manufacturing Platform, forming Huiyi Biomedical’s “trinity” fully autonomous, end-to-end RNA drug R&D platform to accelerate the industrialization of nucleic acid therapeutics.
In addition to delivery technologies, the major challenges and key technical aspects of mRNA development lie in the synthesis and modification stages, which address the primary issues of low stability and susceptibility to degradation of mRNA molecules. For large-scale mRNA synthesis, in vitro transcription (IVT) is currently a highly efficient approach. IVT primarily involves producing mRNA using linear DNA as a template, with key process steps including transcription, chemical modification, and separation and purification. The quality of plasmid DNA used for in vitro transcription, optimization of transcription and modification processes, and control of the reaction conditions are all critical to the final quality of the mRNA bulk substance.
Currently, the main challenges in in vitro transcription (IVT) include batch-to-batch inconsistency, reproducibility of conditions such as heating rates, and human error. Efficient IVT-based production of mRNA drug substance is a key approach to reducing process development and manufacturing costs. Huiyi Biomedical’s RNA sequence design library and IVT synthesis platform ensure consistency, purity, and integrity, delivering excellent protein expression efficiency.
In the production of mRNA vaccines, the ethanol phase containing lipids is mixed with the aqueous phase containing mRNA to create a lipid-supersaturated state, enabling self-assembly into nanoparticles within milliseconds. The most critical process step involves encapsulating the mRNA within lipid nanoparticles (LNPs) to form stable nanoparticles. Currently, this process can be achieved through methods such as microfluidics and jet mixing, with microfluidics being the predominant technology employed in large-scale manufacturing.
Huiyi Biomedical has achieved this by establishing a microfluidic nanodrug manufacturing process platform. By optimizing key technologies in formulation production, the company now possesses development capabilities ranging from small-scale trials to pilot-scale scale-up and even industrialized production.
Based on the “Trinity” Fully Autonomous End-to-End RNA Drug Development Platform,Huiyi Biomedicine has established a multi-pronged pipeline of mRNA vaccines for infectious diseases, including both veterinary and human vaccines, with coverage extending to areas such as cancer immunotherapy and pulmonary drug delivery.
Behind the establishment of the “trinity” RNA drug R&D platform stand three scientists, each specializing in a different field.
Dr. Zhong Tianyi, Co-founder and CEO, previously served as Formulation Director at a leading domestic RNA therapeutics company. With nearly a decade of experience in the R&D and process development of nucleic acid drug delivery systems, he was deeply involved in the dual regulatory submissions to China and the U.S., as well as the clinical sample manufacturing, for China’s first independently developed small nucleic acid drug. He possesses extensive expertise in manufacturing process transfer, CMC quality control, and project management (PMP certified).
Dr. Zhao Lixiang, Co-Founder and CTO, is a Professor of Immunology and Doctoral Supervisor at the Medical College of Soochow University. With extensive research experience in tumor immunology and vaccine development, he has led multiple projects involving the systematic R&D of RNA therapeutics, the development and validation of nucleic acid delivery vectors, and related systemic experiments. Dr. Zhao has published more than 10 SCI-indexed papers on tumor immunology and holds two invention patents for tumor vaccines.
Dr. Jiang Jianhao, Co-Founder and COO, possesses extensive R&D expertise in RNA sequence design and synthesis. He has overseen multiple early-stage mRNA drug development projects and contributed to the sequence design and development of China’s mRNA COVID-19 vaccines during the pandemic.
Each of the three scientists brings extensive expertise in delivery systems, sequence design, and manufacturing process development, “complementing one another perfectly in RNA drug development.” Thus, they have joined forces, forging ahead on a path to break through patent blockades and contributing to the independent research and development of RNA therapeutics in China.