Dr. Zhang Yi of ChemGenX: Advancing Drug Delivery with Dual-Responsive Cationic Nanogels and Next-Gen LNP Platforms

Drug delivery technologies have enabled the development of pharmaceutical products in many fields, including gene therapy, tumor targeting, and vaccines. By enhancing the delivery of therapeutic agents to their target sites, minimizing off-target accumulation, and improving patient adherence, these technologies ultimately promote better patient health. Decades ago, small-molecule drugs were the predominant therapeutic agents.

However, for small-molecule drugs, controlling pharmacokinetic (PK) parameters—particularly drug half-life, solubility, and permeability—remains an unresolved challenge. Meanwhile, off-target toxicity is another issue that cannot be overlooked.

With advances in drug development, the requirements for drug delivery are becoming increasingly stringent, making the innovation of drug delivery carriers an urgent imperative.

An experiment, while conducting postdoctoral research at the Massachusetts Institute of Technology (MIT),Dr. Zhang YiCationic nanogels formed from natural dextran and synthetic dendritic polymers have been developed.

Cationic nanogels contain dual pH- and redox-sensitive linkages. This means that drug release occurs only when the cationic nanogel-based drug delivery system reaches the tumor microenvironment, whereas no drug release takes place in normal cells and tissues.

Thus, the delivered drug can exert a targeted therapeutic effect on the tumor, while sparing healthy cells and tissues from damage caused by drug exposure. Meanwhile, it also indirectly addresses issues such as half-life and drug concentration during the drug delivery process.

Dr. Zhang Yi toldVBInsight Orange Bureau: “This cationic nanogel has demonstrated excellent performance in tumor therapy, and related findings have been successfully published in the journals Nature Materials and Advanced Healthcare Materials.”

This invention propelled Dr. Zhang Yi to prominence at MIT and even within the global pharmaceutical industry, with countless job offers flooding his inbox. Yet he chose to return to China to launch a startup. It is worth noting that transitioning from scientist to entrepreneur constitutes a new adventure in itself.

In 2007, after earning his bachelor’s degree from the Department of Macromolecular Science at Fudan University, Dr. Zhang Yi pursued advanced studies at the University of Texas Southwestern Medical Center, where he conducted research on small-molecule drug delivery. He later completed a postdoctoral fellowship at the Massachusetts Institute of Technology (MIT), shifting his focus to in vivo drug delivery systems for large nucleic acid-based therapeutics, including mRNA.

MIT not only served as the catalyst for his entry into Boston’s industry sector, but also became the key that opened the door to his entrepreneurial venture back in China.

In Boston, he made a close friend—Lin XiangqianXiang Qian is a young entrepreneur who graduated from the Wharton School, with extensive experience in biotech industry investment and life-health enterprise management. He serves as the Chairman and Global CEO of Singapore’s ESCO Group. During a conversation, it was discovered that they shared similar views on the industry:Nucleic acid-based therapeutics will undoubtedly be the most important form of drugs in the next era.

Looking across the pharmaceutical landscape, it is no exaggeration to say that the current era is one of protein-based therapeutics. However, there remain numerous unmet clinical needs that protein drugs cannot adequately address. Consequently, the next wave of technological innovation will inevitably emerge from more upstream and novel frontiers, with nucleic acid therapeutics being a prime example.

Currently, nucleic acid-based therapeutics still face their Achilles’ heel—namely, the issue of drug delivery.

Because all nucleic acid-based drugs have highly unstable structures, naked drugs injected into the human body would reach their half-life within minutes and be rapidly degraded. Therefore, nucleic acid therapeutics require a delivery vehicle capable of effectively targeting the lesion site to protect the drug, thereby maximizing its efficacy in vivo.

This poses a significant challenge for nucleic acid-based therapeutics, both in academic research and in industrial-scale manufacturing.

Only by establishing a robust delivery platform and laying a solid foundation can the skyscraper of nucleic acid-based therapeutics be truly built. Dr. Zhang Yi’s extensive academic and industrial research experience serves as the key to overcoming the critical challenges in drug delivery for nucleic acid-based therapeutics.

Thus, their ideas aligned perfectly, and Dr. Zhang Yi immediately made the decision to decline a lucrative job offer abroad, return to China, and co-foundKemeixin, determined to carve out a niche in China's drug delivery sector.

Because, in his view, collaborating with like-minded partners to accomplish something meaningful is far more precious than money or fame.

It has been proven that their choice was not wrong.

With the outbreak of the COVID-19 pandemic, the number of companies developing nucleic acid-based therapeutics, particularly those specializing in mRNA or lipid nanoparticle (LNP) technologies, has surged both domestically and internationally. Each company claims to possess its own proprietary patents and delivery platforms. The fundamental challenge lies in distinguishing oneself among numerous competitors by developing cutting-edge technologies and advancing them into clinical trials.

Kemeixin, which is engaged in the research and development of engineered red blood cells for immune modulation and non-viral gene delivery based on lipid nanoparticles (LNPs), has filed two patents for cationic lipid structures of entirely independent and original design within less than a year of its establishment. By employing a next-generation structural design strategy, the team rapidly identified lipid structures with superior in vivo performance compared to FDA-approved lipids, thereby paving an expressway toward clinical application.

Dr. Zhang Yi did not consider the attainment of these achievements to have been smooth sailing.

He frankly stated: "Behind every successful clinical trial, there are more than ten failed ones. Success is invariably built upon the lessons learned from failure.“I have also experienced numerous failures; some projects were terminated at the initiation stage, while others fell short at the final hurdle of submitting an Investigational New Drug (IND) application. However, in my view, regardless of the outcome, these experiences are invaluable and rare assets. They will undoubtedly contribute to the development of Kemeixin, or more broadly, to the future advancement of nucleic acid-based therapeutics.”

Drawing from his past experiences, Dr. Zhang Yi has concluded that the two most critical factors for establishing a foothold in the field of nucleic acid-based therapeutics are the mindset of a top-tier organic chemist and hands-on industry experience in translating R&D into production.

If there is a lack of understanding of chemical structures, the newly created designs will also lose their independent intellectual property rights. Some companies introduce new products at an extremely rapid pace, but upon closer examination, these are merely derivatives of existing technologies, without any fundamental innovation or upgrade.

For instance, some U.S. universities are also advancing R&D projects on proprietary cationic structures. However, researchers have failed to grasp the fundamental principles during the design and development process. As a result, the resulting products are largely superficial variations without substantive innovation, incorporating no biodegradable components and lacking chemical structural diversity, which severely limits their subsequent applications.

Therefore, a thorough understanding of chemical structures is essential for the rational design of novel cationic lipid structures. This approach integrates functional considerations for downstream applications at the very outset of the design process.

Secondly, high-throughput screening within the framework of organic chemistry thinking also plays a crucial role in LNP R&D. Due to the complex and highly variable microstructures of LNPs, there is currently a limited understanding of the intrinsic "structure-property" relationships, making it difficult for AI-assisted design tools to provide substantial support. Furthermore, conclusions drawn from limited experimental data are subject to significant limitations.

The only means to address this issue is high-throughput screening. With a sufficiently large database, it becomes possible to analyze and identify truly meaningful "structure–property relationships." In simple terms, under constraints of limited time and resources, those who can synthesize and screen a greater number of structures will be able to advance faster, further, and more effectively.

Kemexin leverages high-throughput synthesis, high-throughput formulation, and high-throughput animal studies to ensure “Kemexin Speed,” maintaining a leading position in the fiercely competitive field of nucleic acid drug delivery.

With his experience spanning from project development to clinical application, Dr. Zhang Yi proudly stated:“As of now, the team I lead is likely the only one in China with experience in advancing LNP products from early-stage research to clinical trials in the United States.”

Before returning to China to launch his startup, Dr. Zhang Yi had already accumulated six to seven years of industry experience, overseeing three pipelines—lipid nanoparticle (LNP)-based pulmonary drug delivery, influenza vaccines, and in vivo gene editing—from research and development through to FDA application submissions. This was a valuable and fortunate experience.

These experiences have enabled the team to readily determine which strategies are viable during LNP development and which “pitfalls” can be avoided. They have also clarified how to adjust the prioritization of R&D tasks at different stages of development.

Dr. Zhang Yi believes that the insights drawn from these failures will help Kemeixin overcome the bottlenecks in targeted delivery more quickly and effectively than other teams.

When asked for advice to researchers currently facing the challenge of translating their findings into practical applications, Dr. Zhang Yi said with a smile:“Research and the market are undoubtedly complementary. Therefore, researchers should seize every opportunity to understand the market, while those working in offices should also spend more time on the front lines in laboratories.”

Although Dr. Zhang Yi also subscribes to the principle of “specialization” in the process of translating research into practical applications, believing that specialized tasks should be entrusted to professionals, he still feels thatResearch perspectives should not be confined solely to one’s own laboratory.

During his academic research career, Dr. Zhang Yi was primarily concerned with whether his findings could be published in high-impact journals. However, after transitioning to the industry sector, he gradually realized that research outcomes incapable of reaching production lines and clinical practice would remain mere theoretical concepts shelved away, failing to truly benefit patients and healthcare providers. Consequently, the translational potential of research results into industrially manufactured drugs has become his primary focus.

In Dr. Zhang Yi’s view, during the process of high-efficiency experimentation,Researchers must not only conduct in-depth academic exploration of their experimental topics but also consider the underlying market demand and the feasibility of practical implementation.

Although Dr. Zhang Yi has transitioned from a scientist to an entrepreneur, he still spends a significant portion of his day “immersed” in the laboratory, reviewing the latest experimental data or engaging in in-depth discussions with frontline researchers.

For Dr. Zhang Yi, whether in his office or the laboratory, his heart remains on the front lines of scientific research, maintaining the closest communication with researchers. He firmly believes that only through a thorough understanding of the results and data at hand can a solid foundation be laid for subsequent experiments, experimental design, and even corporate development planning.