2. Academic Validation
  3. Compacting hyaluronan into nanogels induces an enhanced macropinocytosis in MC38 cells

Compacting hyaluronan into nanogels induces an enhanced macropinocytosis in MC38 cells

  • Int J Biol Macromol. 2025 May;310(Pt 4):143599. doi: 10.1016/j.ijbiomac.2025.143599.
Wei Hou 1,  Xinxin Hao 1,  Jiayi Li 1,  Xiaorong Gou 1,  Hua Guo 2,  Yiyi Zhang 1,  Hong Deng 1,  Weiqi Zhang 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Complex Severe and Rare Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, PR China.
  • 2 State Key Laboratory of Molecular Oncology and Department of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, PR China.
  • 3 State Key Laboratory of Complex Severe and Rare Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, PR China. Electronic address: zwq@ibms.pumc.edu.cn.
PMID: 40306505 DOI: 10.1016/j.ijbiomac.2025.143599
Abstract

Hyaluronan (HA)-based drug delivery system including HA conjugates and nano-formulations have been intensively researched in various biomedical applications due to its excellent biocompatibility and unique biological characteristics. Currently most researches are exploring the targeted drug delivery enabled by HA receptors e.g. CD44-based Cancer targeting, while the contribution of Other cellular uptake pathways in HA-based delivery remains elusive especially for different HA carriers. Here, the cellular uptake of HA in linear form (HA conjugate) and nano-formulation (HA nanogels (NG)) were compared with a focus on macropinocytosis that is actively involved in nutrient scavenging for Cancer cells. Considering the ease of fluorescence in evaluating cellular uptake, Rhodamine b (Rb) dye was employed as a model drug to prepare HA-Rb conjugate and HA/Rb NG. After a comprehensive physiochemical characterization, the cellular uptake of these two HA carriers were compared in MC38 cells with different transport inhibitors, HA synthesis inhibition and nutrient depletion. While macropinocytosis blockage inhibited HA/Rb NG uptake more than HA-Rb, enhancing macropinocytosis either by HA inhibition or serum starvation significantly increased HA/Rb NG uptake. These evidences clearly suggest macropinocytosis contributes differently to the cellular uptake of varied HA carriers, which provides new insights to engineer HA for different drug delivery purposes.

Keywords

Drug conjugate; Drug delivery; Hyaluronan; Macropinocytosis; Nanogels.

Figures
Products