Developing Potent Therapeutics for Liver Cancer Chemoresistance via an RNA Nanotech and Series-Circuit-Christmas-Bulb Mechanism Targeting ABC Transporters.

Liver cancer, particularly hepatocellular carcinoma (HCC), poses significant treatment challenges due to chemoresistance and cancer recurrence. Similar to customs at the border, the liver detoxifies incoming chemicals via efflux pumps and overexpresses ATP-binding cassette (ABC) drug exporters, leading to chemoresistance. ABC contains a multihomosubunit structure and a revolving transport mechanism, actively effluxing drugs from cancer cells, thereby reducing intracellular drug accumulation and therapeutic efficacy. Based on the understanding of the dsDNA translocating mechanism and complete inhibition observed in the multihomosubunit-revolving ATPase of the Phi29 DNA packaging motor, we report here an unprecedented approach to develop a potent HCC drug mimicking the series-circuits of "Christmas light bulbs", as described by the calculation formula: x=(p+q)z=∑M=0Z(ZM)pZ-MqM=∑M=0Z(Z!M!(Z-M)!)pZ-MqM. RNA nanotechnology offers a novel "Christmas light bulb series circuit" strategy, inspired by the Phi29 hexameric RNA-driven DNA packaging motor, in which targeting a single subunit completely inhibits the entire cassette. The concept has been validated by delivering Paclitaxel and miRNA via RNA nanostructures to inhibit the homomeric multisubunit ABC drug efflux pump P-gp in HCC in a mouse model. The programmable and multivalent nature of RNA nanotechnology enables the codelivery of multiple high-payload therapeutics, combined with liver-targeting ligands such as GalNAc, thereby achieving synergistic anticancer effects. This review highlights the mechanistic insights into potent HCC drug design, the advantages of RNA nanotechnology, and the structure-function relationship of ABC and other ATPase transporters, emphasizing a targeted strategy to overcome chemoresistance in liver cancer.