Hydrophobic interactions enhance doxorubicin delivery from hyaluronic acid nanogels

This study introduces a novel targeted chemotherapy approach employing biocompatible nanogels engineered from hyaluronic acid (HA) and pitaya-derived DNA. Both polymers were functionalized with aldehyde groups, enabling crosslinking and subsequent encapsulation of doxorubicin (DOX). The incorporation of DNA significantly enhanced DOX loading, achieving a remarkable encapsulation efficiency of 93.3%. Notably, the integration of a hydrophobic 4,4'-dithiodianiline (DTD) linker facilitated controlled drug release within the reductive tumor microenvironment, with 36% of DOX released within 24 h in response to glutathione (GSH). These nanogels demonstrated targeted delivery to CD44-overexpressing cancer organoids, exhibiting a 6.7- to 15-fold increase in cellular uptake compared to free DOX. This enhanced intracellular DOX delivery significantly increased apoptosis in both cancer cells and organoids, as evidenced by increased condensed DNA and a 1.86- to 6.9-fold increase in poly ADP-ribose polymerase (PARP) expression. Importantly, hydrophobic interactions between the DTD linker and the cell membrane were found to significantly contribute to the efficient cellular uptake of the nanogels, resulting in a 2.6- to 9.1-fold reduction in IC₅₀ values compared to free DOX. These findings highlight the potential of HA-based nanogels with cleavable linkers as promising platforms for targeted drug delivery and enhanced cancer therapy.