Charge reversible hyaluronic acid-based drug delivery system with pH-responsive dissociation for enhanced drug delivery

[Display omitted] •A pH-sensitive (IMI/Zn2+)-HA-PLL-DMMA system is synthesized via Zn coordination.•The (IMI/Zn2+)-HA-PLL-DMMA system can detach DMMA moieties to expose positive charge.•The (IMI/Zn2+)-HA-PLL-DMMA system shows enhanced drug delivery. Improving the efficiency of drug delivery is one of the most important goals in the field of drug delivery. One strategy for drug delivery efficiency is to make the drug delivery system capable of charge reversal. In this study, we used hyaluronic acid (HA) as the skeleton to anchor dimethylmaleic anhydride-modified polylysine (PLL-DMMA) and N-(3-Aminopropyl)-imidazole (IMI) to construct a pH-sensitive (IMI/Zn2+)-HA-PLL-DMMA system via Zn coordination. The (IMI/Zn2+)-HA-PLL-DMMA system can detach DMMA moieties and expose PLL with a positive charge in the acidic tumor microenvironment (TME), which enhances cellular uptake in cancer cells through charge reversal. Once the drug-loaded (IMI/Zn2+)-HA-PLL-DMMA enters cancer cells, it specifically responds and disassembles in the acidic TME, resulting in drug release and inhibition of cancer cell viability. The (IMI/Zn2+)-HA-PLL-DMMA system is designed to regulate drug release behavior with Zn2+ and IMI groups as control units. The HA-based system shows synergistic selective drug delivery in suppressing tumor cells and has potential in cancer therapy.