Glycosylated quercetin/cisplatin combinational nanodrugs for enhanced oxidative therapy and chemotherapy

Drug self-assembly technology holds great potential for drug delivery; however, its practical application is often hindered by poor dispersibility, instability, and suboptimal therapeutic efficacy in monotherapy. To address these limitations, we developed a co-assembly strategy based on glycosylation and coordination crosslinking. Lactobionic acid (LA)-modified quercetin (QC) derivatives were synthesized via phenylboronic acid ester bonds and further assembled with cisplatin (CDDP) through Pt-O coordination bonds, forming LA-QC@Pt/NPs. In vitro studies revealed that hydrophobic/π-π interactions and Pt-O crosslinking significantly enhanced the stability of the nanodrug during dilution, long-term storage, and freeze-thaw cycles. Under acidic conditions, these interactions were disrupted, resulting in rapid drug release (86.85 ± 2.74 % of CDDP and 60.83 ± 1.15 % of QC within 24 h). Moreover, LA greatly improved the aqueous dispersibility and active targeting ability of the nanodrug, thereby enhancing cellular uptake in hepatocellular carcinoma cells and increasing cytotoxicity (IC₅₀ of QC and CDDP decreased by 70-72 % and 54-75 %, respectively). Mechanistically, the nanodrug amplified oxidative stress by inhibiting glutathione peroxidase (GSH-Px), exacerbated DNA damage by reversing glutathione S-transferase π (GST-π)-mediated CDDP detoxification, and blocked AKT1/NF-κB-mediated DNA repair. In vivo studies showed that LA-QC@Pt/NPs extended the half-life of CDDP to 2.17 h, inhibited tumor growth by approximately 66 %, and mitigated the systemic toxicity of CDDP. Thus, this glycosylation-driven self-assembly platform is a promising strategy for multi-drug delivery and combination therapy.