Bioresponsive Nucleic Acid Base Pair-Inspired Nanogels for Codelivery of Chemo-/Protein Drugs in Targeted Cancer Therapy

Codelivery of chemo- and protein drugs enhances efficacy but faces challenges from physicochemical differences and inefficient release. We fabricated dual-responsive and tumor-targeting nucleic acid base-inspired nanogels (DTNANGs) for the <i>in vivo</i> codelivery of gemcitabine (Gem) and cytochrome C (CC). The nanogels were engineered through pH-sensitive base-pairing cross-linking between guanine- and cytosine-modified hyaluronic acid derivatives. DTNANGs achieved high drug-loading efficiency (96.3% for Gem, 94.5% for CC). <i>In vitro</i> and <i>in vivo</i> experiments confirmed that DTNANGs demonstrated superior CD44-mediated tumor-targeting capacity, enhanced tumor accumulation, improved cellular uptake, and fast endolysosomal escape. Additionally, CC-loaded DTNANGs increased cell apoptosis by 75.5% in A549 cells, outperforming monotherapy. Moreover, <i>in vivo</i> evaluations in A549 tumor-bearing mice revealed that they significantly inhibited tumor growth (70% inhibitory rate) compared to other control groups, while exhibiting negligible systemic toxicity. Our study lays the groundwork for controlled, effective codelivery of chemo- and protein drugs, enabling precision cancer therapy.