Reversal Drug Resistance of Tumor Cells by Manipulating its Membrane Heterogeneity through High Spatially Resolved Heating

Multidrug resistance (MDR) presents a substantial challenge to the therapeutic efficacy of cancer chemotherapy. A common trait of drug-resistant cells is decreased cell membrane permeability, hindering the uptake of therapeutic agents. Additionally, these cells frequently overexpress drug efflux pumps that actively expel the drugs, leading to reduced intracellular accumulation. In this study, we introduce a high spatially resolved, domain-specific, mild heating strategy to counteract drug resistance using DNA nanodevices. This strategy aims to manipulate the membrane heterogeneity by increasing cell membrane permeability and decreasing the expression of drug efflux pumps. The DNA nanodevices (termed DNA nanoheaters) with specific domain affinity anchor distinct cell membrane domains (raft/nonraft) and elevate the local lipid environmental temperature upon near-infrared (NIR) laser exposure. This elevation in local lipid temperature modifies key biophysical membrane features of Doxorubicin-resistant tumor cells, resulting in a two-order magnitude decrease in IC₅₀. Notably, our approach diverges from conventional methods that depend on the delivery of pharmacological reversal agents. Instead, we emphasize modulating the membrane properties of drug-resistant cells through mild physical stimuli, offering a potential reduction in systemic toxicity associated with chemotherapy.