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

The development of nanomedicine that can be efficiently internalized by drug-resistant cancer cells still presents a daunting challenge due to the low uptake capacity caused by various drug resistance-related factors on the cell membrane. Herein, we engineered the surfaces of glycan nanocarriers with negative, neutral, and gradient positive charges, and discovered that positively charged nanocarriers can be anchored onto the cell membrane through electrostatic attraction and thus be efficiently internalized by drug-resistant cancer cells. In contrast, drug-resistant cancer cells do not readily uptake neutral or negatively charged nanocarriers. By proposing a concentric ring fluorescence coefficient (CRFC), we were able to quantify the cell membrane anchoring capabilities of the nanocarriers and found that positively charged nanocarriers have a much stronger anchoring ability toward drug-resistant cell membranes than their neutral and negatively charged counterparts. Interestingly, with the increase of positive charge, the ability of the nanocarriers to become anchored onto cell membranes was further enhanced, thus confirming that electrostatic attraction plays a crucial role in the membrane-anchoring guided cellular uptake. The method of endowing nano-objects with this charge-attracting capability towards negatively charged cell membranes to drive membrane-anchoring mediated cellular uptake illustrates its potential as a universal strategy for engineering nanocarriers to promote the uptake of nanodrugs into drug-resistant cancer cells and thus improve the therapeutic effect.