A charge-reversible hyaluronic acid prodrug nanoplatform for synergistically enhanced tumor-targeted doxorubicin delivery

Conventional nanocarriers often face challenges of insufficient tumor specificity and poor cellular internalization. To overcome these limitations, we developed an all-in-one prodrug nanoplatform based on hyaluronic acid (HA) that synergistically integrates active targeting, pH-responsive charge reversal, and controlled drug release. Doxorubicin (DOX) was covalently conjugated to oxidized HA via a pH-sensitive imine bond, while a charge-reversal polymer (PLL-DMMA) was grafted onto the HA backbone. This design enables CD44-mediated active targeting toward cancer cells. Crucially, the nanoplatform exhibits a smart charge-reversal characteristic: maintaining a negative surface charge (−32.8 mV) at physiological condition (pH 7.4) for extended circulation, while switching to positive (+16.5 mV) in the acidic tumor microenvironment (pH 6.5) to enhance cellular uptake. In vitro studies demonstrated significantly improved internalization in CD44-overexpressing MKN-45 cells compared to SNU-216 cells with low CD44 expression. The release profile showed high stability at pH 7.4 (<5% release in 5 days) and rapid drug release at endo/lysosomal pH (61.6% at pH 5.0). Cytotoxicity assays confirmed enhanced efficacy of the charge-reversed formulation, with lower IC 50 values in both cell lines. This multifunctional prodrug nanoplatform represents a promising strategy for precision cancer chemotherapy through synergistic enhancement of tumor targeting and intracellular drug delivery. In this study, we developed an all-in-one prodrug nanoplatform based on hyaluronic acid (HA) that synergistically integrates active targeting, pH-responsive charge reversal, and controlled drug release. In vitro studies demonstrated significantly improved internalization in CD44-overexpressing MKN-45 cells compared to SNU-216 cells with low CD44 expression. Cytotoxicity assays confirmed enhanced efficacy of the charge-reversed formulation, with lower IC50 values in both cell lines. This multifunctional prodrug nanoplatform represents a promising strategy for precision cancer chemotherapy through synergistic enhancement of tumor targeting and intracellular drug delivery. Download: Download high-res image (132KB) Download: Download full-size image