Zhejiang University to Transfer Two Gene-Engineered Microbial Patents for 800,000 RMB

Recently, Zhejiang University released a public notice on patent commercialization, proposing to transfer its“A Genetically Engineered Bacterial Strain for Selective Production of Retinol, Its Construction Method, and Applications”and two other patents, transferred through listing for trading, with a transaction amount ofRMB 800,000. The formerUsing β-carotene-producing strains as the starting strain, the optimized retinol yield reached 401.65 mg/L; the latter, using retinal-producing yeast as the chassis, achieved a maximum retinoic acid yield of 99.31 mg/L. Both technologies address the pain points of traditional production methods and can be widely applied in the cosmetics and pharmaceutical industries, offering safety, high efficiency, and environmental friendliness. The inventors of this patent are Ye Lidan and her team.

Acne, a highly prevalent dermatological condition worldwide, affects up to 85% of adolescents and 12%-14% of adults. Patients often suffer from recurrent inflammatory papules, with ruptured pustules leading to permanent scarring or hyperpigmentation, severely impacting their appearance and psychological well-being. Meanwhile, disorders of keratinization such as ichthyosis and palmoplantar keratoderma, characterized by impaired skin barrier function, cause patients to endure chronic discomfort including dryness, scaling, and pruritus, for which existing treatments offer no cure.

Retinoic AcidAs the active metabolic core product of vitamin A, retinoic acid precisely regulates the transcription of downstream target genes by binding to nuclear retinoic acid receptors (RAR) and retinoid X receptors (RXR) to form heterodimers. It directly participates in the proliferation, differentiation, and immune balance of skin cells, inhibiting the excessive proliferation of keratinocytes and reducing hyperkeratotic obstruction of hair follicle sebaceous ducts, while also modulating the release of inflammatory cytokines. Thus, it serves as a key active substance in the treatment of dermatological conditions such as acne and keratinization disorders. Retinol, the alcohol form of vitamin A, is gradually converted into retinoic acid via dehydrogenases in the body to exert its physiological effects. Its mild activity profile makes it a core ingredient in cosmetic applications for moisturizing, anti-aging, and improving dull skin tone, offering higher safety and sustaining rising market demand.

Meanwhile, clinical demand for retinoid drugs extends beyond efficacy alone, imposing stringent requirements on purity and active stability. Excessive impurities may trigger adverse effects such as skin irritation and allergic reactions, while insufficient potency can lead to prolonged treatment courses and disease recurrence. This contradiction has become a core pain point in clinical therapy.

As the market gap for high-purity retinol and tretinoin continues to widen,Scale-up Production of Chemical Synthesis Pathwaysweaknesses are gradually becoming apparent. Namely,Insufficient selectivity for the all-trans isomer, the cis-isomer content is as high as 28%–80%, necessitating additional costly investment in optical isomer purification; the production process is energy-intensive and generates numerous by-products, which not only increases production costs but also poses environmental pollution risks.

Although microbial synthesis is regarded as a superior option, existing technologies still exhibit significant limitations. In Escherichia coli-based synthesis systems, endotoxin residues inherent to the host are difficult to eliminate completely, failing to meet the safety standards for pharmaceuticals and high-end cosmetics. Furthermore, the retinoic acid yield in E. coli is only 3.46 ± 0.16 mg/L, which is far from sufficient for large-scale production needs. Meanwhile, yeast host systems, which offer higher synthetic efficiency, have previously reported maximum yields of less than 80 mg/L.

Moreover, in addition to low synthesis efficiency, existing retinoic acid synthesis protocols suffer from issues such as product susceptibility to oxidation and the need for complex process control during fermentation, thereby hindering industrial-scale implementation. Consequently, there is an urgent need for innovation within the industry to overcome these challenges.

In this proposal, both patented technologies are based onGenetic Engineeringas the core, throughOptimization of Chassis Strains, Metabolic Pathway Reconstruction, and Fermentation Process Innovation, specifically addressing the pain points of traditional production and achieving efficient and safe synthesis of retinol and retinoic acid.

Retinol Production Technology Based on the β-Carotene-Producing Engineered Strain Ycarot-02 as the Chassis, innovatively constructing a proprietary synthetic pathway—precisely integrating β-carotene 15,15'-dioxygenase, aldehyde reductase, retinol dehydrogenaseThree key enzyme-encoding genes raise the proportion of retinol in total vitamin A to as high as99.86%, addressing the industry-wide challenge of isomer contamination in traditional synthesis. To overcome production capacity limitations, the technology employs a triple metabolic optimization strategy:

First, the gene encoding a mutant geranylgeranyl diphosphate synthase is introduced to enhance precursor supply, while NADH kinase is truncated and its mitochondrial targeting peptide is removed to enable efficient cytosolic generation of the coenzyme NADPH.

Second, knockout of the transcriptional repressor gene in the mevalonate pathway alleviated metabolic inhibition, ultimately driving retinol production to 401.65 mg/L, representing a more than fivefold increase over existing microbial synthesis technologies.

Thirdly, in view of the susceptibility of retinol to oxidation, the ferrous ion concentration was optimized to 1.44 mM to activate BLH enzyme activity. Coupled with the antioxidant butylated hydroxytoluene (BHT) and a dodecane two-phase fermentation system, this approach not only ensured product stability but also simplified the separation process, thereby achieving the dual goals of “high yield + high purity.”

The retinoic acid production technology employs the yeast strain Y03, which produces retinal and has a higher biosafety profile, as the chassis. It innovatively clones the endogenous aldehyde dehydrogenase-encoding gene from Saccharomyces cerevisiae for homologous expression.The catalytic efficiency is significantly superior to that of heterologous enzymes; through gradient integration of 1–4 gene copies combined with MOT3 gene knockout, the retinoic acid titer reached 99.31 mg/L, representing a 28-fold increase over existing Escherichia coli synthesis systems, while avoiding safety risks associated with endotoxin residues and phage contamination. In terms of separation processes, an innovative approach was adoptedDodecaneorOlive OilAs an extractant, it enables the direct extraction of intracellular retinoic acid into the organic phase during fermentation, with extracellular secretion accounting for up to 55.05%. This allows for efficient product collection without cell disruption, significantly reducing purification costs. The process exhibits strong compatibility, allowing flexible switching between single-phase and two-phase fermentation modes. Standardized conditions—cultivation at 200–250 rpm and 28–30°C in the dark for 72–84 hours—offer both technical feasibility and economic practicality.

Leveraging precise design and process optimization through genetic engineering, these two technologies provide high-purity therapeutic raw materials for the pharmaceutical sector and introduce safer active ingredients to the cosmetics industry, effectively addressing the market supply gap for high-quality vitamin A derivatives.

Retinol, retinoic acid, and their derivatives, as core ingredients offering physiological regulation, skincare, and therapeutic benefits, have gained increasing prominence in recent years across the cosmetics, pharmaceuticals, and biomanufacturing sectors. From innovations in raw material production technologies to enhancements in the efficacy of end products, industry competition has exhibited“Technological Breakthroughs + Application-Specific Segmentation”the dual-track pattern.

Guangzhou Shimei Cosmetics Co., Ltd. Firming and Anti-Wrinkle Composition:This product contains 0.2–0.5 parts of growth factor promoters (optionally including hydroxypinacolone retinoate, etc.), 1 part of Litsea cubeba fruit extract, and 0.02–0.08 parts of sodium DNA derived from salmon sperm. These three components work synergistically to address skin laxity caused by deep-layer protein loss, slowed epidermal cell renewal, and reduced moisture retention in the stratum corneum, thereby improving skin wrinkles through multiple mechanisms. By combining retinoic acid derivatives with natural plant extracts and bioactive ingredients, this formulation mitigates the irritation associated with single-ingredient use, enhances the synergistic anti-wrinkle and firming effects, precisely meets the anti-aging needs of mature skin, and expands the application scenarios of retinoic acid-based ingredients in the premium skincare sector.

Sichuan Zerun Jiamei Cosmetics Co., Ltd. Botanical Seed Oil Blend (For Essence Oil):Comprising Component A (isononyl isononanoate, Ormosia henryi bark extract), Component B (oil-phase solvent), and Component C (1.8–2.2 parts of hydroxypinacolone retinoate, Candida bombicola fermentation oil, sweet almond seed oil, etc.). Through formula optimization, the product focuses on enhancing the penetration and absorption efficiency of the essential oil in the stratum corneum. Addressing the technical challenges associated with the strong lipophilicity and insufficient skin penetration of retinoic acid derivatives, this product constructs a penetration-enhancing system using plant seed oils as carriers. This approach improves bioavailability while ensuring ingredient stability, providing a formulation solution for the application of retinoic acid derivatives in dosage forms such as essential oils.

From technological innovations in raw material production to the segmentation of end-use scenarios, competition among retinol/retinoic acid products has entered a phase of refinement. In the future, “high purity and low irritation” on the technology front, coupled with “scenario-based and personalized” applications, will become the core competitive factors, driving the industry’s transition from “ingredient stacking” to “technology-enabled, precision-efficacy” solutions.