Abstract
The management of toxicity, and the fulfillment of safety requirements are considered as the most prominent challenges associated with cancer drug delivery. This study introduces a novel pH-responsive nanoparticle system based on ZIF-8 for the co-delivery of a ruthenium(ii) polypyridyl complex (RuPIP) and olaparib (Olap), which is designed for enhanced therapeutic efficacy and reduced systematic toxicity. To improve their biocompatibility and targeting, the nanoparticles were surface-coated with folic acid ligand, yielding the final RuPIP-Olap@ZIF-8-FA formulation. The RuPIP-Olap@ZIF-8 nanoparticles were fabricated through a rapid, eco-friendly method, and they achieved high co-loading capacities of 20.59% ± 1.38% for RuPIP and 10.77% ± 1.00% for Olap, as confirmed by HPLC analysis. In vitro, the FA-coated dual-drug system exhibited clear pH-responsive behaviour, releasing 80% of RuPIP and 99% of Olap at pH 5.0, compared with 32% and 29%, respectively, at pH 7.4 within 48 hours. The FA-coated RuPIP-Olap@ZIF-8 system also showed markedly enhanced cytotoxicity against the MCF-7 and MDA-MB-231 cell lines, reducing the cell viability to 11.38% and 13.48%, respectively. In comparison to the non-coated dual-drug system, the FA-coated dual-drug system did not induce lethality to 75% of embryos (LC(50) > 250 µg mL(-1)) with significant improved survivability (90%) until 120 h of incubation. Results showed that RuPIP-Olap@ZIF8-FA did not cause significant malformations, even at elevated concentrations, and did not present aggregation issues toward healthy embryos. These findings establish RuPIP-Olap@ZIF-8-FA as a promising dual-drug nanocarrier capable of targeted delivery, pH-triggered release, and distinct therapeutic pathways. Its high loading efficiency, simplicity, and improved safety profile highlight its strong potential for advancement toward clinical translation.