Facile synthesis of amorphous coordinated metal–drug frameworks for cancer immunotherapy

Phosphoinositide kinase containing FYVE-type zinc finger (PIKfyve) inhibitors show potential immunomodulatory activity but suffer from poor tumor targeting and formulation challenges. Herein, we screened a series of PIKfyve inhibitors and engineered selected PIKfyve inhibitor into amorphous metal-drug frameworks (aMDFs) through coordination chemistry between pyridine/imidazole moieties and tailored metal nodes verified by theoretical simulations and nuclear magnetic resonance spectroscopy. The resulting aMDFs showed enhanced stability and processability, enabling efficient encapsulation into solid lipid NPs (HF@SLN). In both orthotopic and subcutaneous murine pancreatic cancer models, HF@SLN demonstrated superior tumor growth inhibition over free PIKfyve inhibitors. HF@SLN treatment was associated with increased transcription factor EB (TFEB) expression, accompanied by enhanced cytotoxic T cell infiltration and improved antitumor immune responses in both murine and human pancreatic tumor samples. This study demonstrates the feasibility of employing carrier-free aMDFs for the formulation and delivery of pyridine- and imidazole-containing therapeutics.