An intrinsically pH-sensitive phosphazene based nickel MOF for high-efficiency tumor-targeted co-delivery of paclitaxel and curcumin

The persistent challenges of multidrug resistance and systemic toxicity in cancer chemotherapy necessitate the development of intelligent, tumor-targeted co-delivery systems. Herein we report a novel nickel-based metal-organic framework (CUR + PTX@Ni-MOF) engineered with a phosphazene-derived ligand for the pH-responsive co-delivery of paclitaxel (PTX) and curcumin (CUR). The framework integrates a hexachlorocyclotriphosphazene (HCCP)-based linker featuring an intrinsically acid-labile P3N3 core enabling controlled degradation within the acidic tumor microenvironment (TME). The Ni-MOF exhibits a high BET surface area (177.118 m 2 /g) and a mesoporous architecture facilitating exceptional dual-drug loading capacities of 56.15% for CUR (96.3% encapsulation efficiency, EE) and 26.18% for PTX (43.01% EE). In vitro release studies demonstrated minimal drug leakage at physiological pH (7.4), while triggered, sustained release was achieved under acidic conditions (pH 6.5 and 5.0) with maximum cumulative releases of 75.42% for CUR and 49.35% for PTX at pH 5.0. Cellular assays confirmed high biocompatibility with normal LO2 hepatocytes (>80% viability) and potent, synergistic cytotoxicity against HeLa cancer cells driven by enhanced cellular uptake and apoptosis induction. This work establishes CUR + PTX@Ni-MOF as a promising, intrinsically pH-responsive platform for targeted and synergistic combination chemotherapy.