Article Impact Level: HIGH Data Quality: STRONG Summary of Cell, S0092867425003861. https://doi.org/10.1016/j.cell.2025.03.036 Dr. Zhengyu Wang et al.
Points
- This study discovered that CD36, a membrane receptor involved in lipid transport, facilitates the endocytic uptake of larger and polar molecules, such as PROTACs, which was previously thought impossible.
- The researchers used a chemical endocytic medicinal chemistry strategy to optimize drug binding to CD36, leading to enhanced cellular uptake and increased potency, particularly for proteolysis-targeting chimeras (PROTACs).
- The new method significantly improved drug solubility, permeability, and efficacy, particularly for PROTACs, which are challenging to deliver due to their size. It enhanced both in vitro and in vivo effectiveness.
- The findings suggest that leveraging CD36 for drug delivery opens new possibilities for treating diseases like cancer and neurological disorders, especially for large molecules that have historically been difficult to administer effectively.
- The study also highlighted that CD36 expression varies between individuals and tissues, which could lead to precision medicine approaches where treatments are tailored based on CD36 levels for more personalized therapies.
Summary
This study explored a novel approach to improving drug delivery, particularly for large and polar molecules that struggle with cell membrane penetration. By focusing on CD36, a membrane receptor typically involved in lipid transport and metabolism, the research team discovered that CD36 also facilitates the endocytic uptake of larger molecules, such as proteolysis-targeting chimeras (PROTACs), with molecular weights ranging from 543 to 2,145 Da. This new finding challenges the traditional belief that molecules above 500 Da cannot effectively enter cells. Using biotinylated probe-based techniques, the team enhanced the engagement between CD36 and drugs, leading to more efficient internalization of these molecules and increased potency.
The team implemented a chemical endocytic medicinal chemistry strategy, which optimized drug binding to CD36. This approach demonstrated significant improvements in drug uptake, especially for PROTACs, a class of drugs that requires targeted interactions with proteins to achieve therapeutic effects. When this method was applied, the compounds exhibited enhanced cellular uptake, which was validated in preclinical models. The results indicated that the compounds delivered using this strategy were far more effective at reaching their targets in vitro and in vivo. Importantly, this technique was also shown to improve the solubility and permeability of the drugs, typical challenges in drug delivery.
These findings have broad implications for drug development, particularly for diseases that have previously been difficult to treat with traditional methods. By leveraging CD36’s role in cellular uptake, this strategy opens new possibilities for enhancing the bioavailability of large molecules, including drugs to treat cancer and neurological disorders. The team also found that CD36 expression varies between individuals and tissues, offering a potential route for precision medicine, where treatments can be tailored based on CD36 levels. This breakthrough may significantly influence future approaches in pharmacology and regulatory frameworks for drug approvals.
Link to the article: https://www.cell.com/cell/fulltext/S0092-8674(25)00386-1
References Wang, Z., Pan, B.-S., Manne, R. K., Chen, J., Lv, D., Wang, M., Tran, P., Weldemichael, T., Yan, W., Zhou, H., Martinez, G. M., Shao, J., Hsu, C.-C., Hromas, R., Zhou, D., Qin, Z., Lin, H.-K., & Li, H.-Y. (2025). CD36-mediated endocytosis of proteolysis-targeting chimeras. Cell, S0092867425003861. https://doi.org/10.1016/j.cell.2025.03.036
