Electrostatic attraction-directed membrane anchoring as a universal tool to enhance nanocarrier uptake into drug-resistant cancer cells

The development of drug resistance—an inevitable outcome as cancers evolve—remains a major obstacle to effective treatment. Overexpression of drug resistance-related proteins and the unique properties of drug-resistant cell membranes make the efficient internalization of nanomedicines a persistent challenge. Surface charge engineering has emerged as a powerful strategy in nanomedicine design, where electrostatic interaction-mediated membrane anchoring of nanocarriers offers a breakthrough in overcoming drug resistance.

A team of materials scientists led by Professor Hongjing Dou at Shanghai Jiao Tong University has now reported a universal strategy that harnesses electrostatic attraction-directed membrane anchoring to enhance drug-resistant cancer therapy. Drawing inspiration from the negatively charged nature and drug-pumping activity of resistant cancer cell membranes, the researchers engineered nanocarriers with varying charge gradients. This approach bridges the gap between charged nanocarriers and resistant cells, advancing both the study of drug resistance mechanisms and the development of more effective nanomedicine platforms.

In their study, the team investigated how nanocarriers with different surface charge gradients interact with heterogeneous cancer cells, with a focus on drug-resistant populations. To measure these interactions, they introduced the Concentric Ring Fluorescence Coefficient (CRFC) as a new tool to quantify membrane anchoring. The results revealed that negatively charged and neutral nanocarriers are efficiently taken up by drug-sensitive cancer cells but show minimal uptake in resistant cells. By contrast, positively charged nanocarriers anchor to resistant cell membranes via electrostatic interactions, enabling efficient internalization. Using glycan-based nanocarriers, the researchers identified three key factors underlying this behaviour: (1) clathrin-mediated endocytosis pathways, (2) cytoskeletal structure-related dynamics, and (3) reduced membrane fluidity caused by P-glycoprotein. They further validated the versatility of this platform across multiple drug-sensitive and drug-resistant cancer cell types, as well as clinically relevant drug-resistant models. These findings highlight the potential of charge-gradient nanocarriers as a generic platform for treating diverse drug-resistant cancers. Moreover, by exploiting the strong anchoring of highly positively charged nanocarriers, scientists gain a valuable tool for probing cancer drug resistance behaviours and mechanisms, opening new avenues for overcoming one of oncology’s greatest challenges.

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Nano Research is a peer-reviewed, open access, international and interdisciplinary research journal, sponsored by Tsinghua University and the Chinese Chemical Society, published by Tsinghua University Press on the platform SciOpen. It publishes original high-quality research and significant review articles on all aspects of nanoscience and nanotechnology, ranging from basic aspects of the science of nanoscale materials to practical applications of such materials. After 18 years of development, it has become one of the most influential academic journals in the nano field. Nano Research has published more than 1,000 papers every year from 2022, with its cumulative count surpassing 7,000 articles. In 2024 InCites Journal Citation Reports, its 2024 IF is 9.0 (8.7, 5 years), and it continues to be the Q1 area among the four subject classifications. Nano Research Award, established by Nano Research together with TUP and Springer Nature in 2013, and Nano Research Young Innovators (NR45) Awards, established by Nano Research in 2018, have become international academic awards with global influence.