The blood-brain barrier (BBB), a critical defense guarding the central nervous system, effectively blocks harmful substances but also severely impedes the entry of therapeutic drugs into the brain, constituting a core bottleneck in treating neurological diseases. Although lipid nanoparticles (LNPs) have matured for targeted delivery to organs like the liver, spleen, and lungs, their application to the brain remains challenging due to BBB obstruction, inadequate stability of nucleic acid therapeutics, and immune responses.

Professor Zhihong Jiang's team from Macau University of Science and Technology and Professor Chong Li's team from Southwest University pioneered an innovative approach, drawing key inspiration from the structure of the natural compound Berberine (BE) and its stable tetrahydro derivatives. Leveraging berberine's characteristic tetrahydroisoquinoline scaffold, the research team designed and constructed a novel class of ionizable lipid molecules.

These molecules ingeniously integrate multiple advantages:

1. Efficient Brain-Targeting Mechanism: Utilizing the inherent targeting capability of berberine-like molecules to bind the dopamine D3 receptor (D3R), which is widely distributed in the brain (particularly in Alzheimer's disease-relevant regions), the innovatively developed BE-ST lipid nanoparticles can effectively traverse the traditionally impermeable BBB via D3R-mediated endocytosis.

2. Superior Nucleic Acid Stability and Loading: Overcoming the limitations of traditional LNPs primarily reliant on electrostatic interactions, the novel alkaloid-based lipids engage in unique intercalation and self-assembly with the polyadenylic acid [poly(A)] tail of mRNA. This forms highly stable complexes, significantly enhancing the loading capacity for nucleic acid drugs and their stability during delivery.

3. Intrinsic Bioactivity and Low Immunogenicity: The material inherently inherits beneficial pharmacological properties from berberine, such as antioxidant and anti-inflammatory activities, conferring neuroprotective potential. Concurrently, by employing organic acids to neutralize positive charges, non-specific adsorption is effectively reduced, optimizing targeting efficiency while lowering immunogenicity. This results in excellent biocompatibility and safety for long-term use.

Compared to the limited efficiency gains of traditional brain-targeting strategies, the BE-ST platform demonstrates significant advantages: In both in vitro cellular uptake and in vivo biodistribution studies, BE-ST nanoparticles exhibited far superior BBB penetration capability and brain tissue-specific enrichment compared to control groups. Furthermore, the platform successfully delivered therapeutic nucleic acids (e.g., siRNA) or small molecule drugs in mouse models of various major brain diseases, including Alzheimer's disease, glioma, and cryptococcal meningitis, consistently showing marked therapeutic efficacy and validating its robust disease intervention capabilities. The BE-ST platform is not only suitable for siRNA but also shows promising potential for mRNA and small molecule drug delivery to the brain, highlighting its broad applicability as a modular brain-targeting platform.

The advent of the BE-ST platform signifies a major leap forward in brain-targeted delivery technology. Its innovative design, based on a natural bioactive molecule, successfully integrates critical elements: efficient BBB penetration, stable nucleic acid loading, synergistic pharmacological activity, and low immunogenicity. Future efforts, including further optimization of the lipid structure and exploration of strategies like modulating cerebral blood flow, hold promise for achieving even more precise and efficient brain-targeted therapies. This versatile platform, characterized by high efficiency, stability, and multifunctionality, offers a promising new therapeutic strategy and hope for Alzheimer's disease, brain tumors, CNS infections, and even broader neuropsychiatric disorders, ushering in a new era for brain gene and drug therapy.

The successful development and translation of such innovative delivery systems rely heavily on high-quality, high-performance lipid materials. In this domain, Sinopeg stands as a significant player in both domestic and international lipid markets. Possessing proprietary intellectual property for patented lipid architectures and mature, stable production processes, Sinopeg provides global research institutions and pharmaceutical companies with a diverse range of high-performance lipid raw materials. Our products have been extensively validated in cutting-edge fields like nucleic acid drug delivery and novel vaccine development. The professional lipid solutions offered by Sinopeg undoubtedly represent a reliable choice for accelerating R&D progress and ensuring product performance and safety! We welcome inquiries and collaborations.

Reference：Bian, X., Guo, Q., Yau, LF. et al. Berberine-inspired ionizable lipid for self-structure stabilization and brain targeting delivery of nucleic acid therapeutics. Nat Commun 16, 2368 (2025). https://doi.org/10.1038/s41467-025-57488-0

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