Zeolitic Imidazolate Framework-8 (ZIF-8) as a versatile platform for targeted cancer drug delivery: A brief review

Zeolitic Imidazolate Framework-8 (ZIF-8), a biocompatible metal-organic framework built from zinc ions and 2-methylimidazole linkers, has attracted substantial interest as a pH-responsive nanocarrier in cancer drug delivery. This review systematically examines more than thirty ZIF-8-based drug delivery systems across five principal modification strategies: receptor-mediated active targeting, biomimetic and protein-based surface engineering, multi-modal therapeutic integration, polymer-based stealth design, and biologic cargo encapsulation. The unifying release mechanism across all reviewed systems is the acid-catalysed protonation of imidazolate linkers, triggering controlled framework disassembly at tumour microenvironmental pH (6.5–7.0) and endolysosomal pH (<=5.0) while preserving cargo integrity at physiological pH (7.4). Quantitative assessment of the reviewed literature demonstrates measurable therapeutic advances attributable to progressive surface engineering: encapsulation efficiency has increased from 21.44% in basic ZIF-8@DOX formulations to 77% (Fe3O4@ZIF-8/DOX) and 94% (ZIF-8/SrSe@DOX), while in vivo tumour inhibition rates have advanced from 85.46% (eM-cRGD@DOX@ZIF-8) and 90.5% (HA@VK3& L -Arg@ZIF-8) to 97.32% (ID@ZIF-8@HPG, laser-activated). To integrate these findings into a coherent translational logic, this review introduces the ZIF-8 Cancer Nanomedicine Design Persistent translational barriers include modest drug loading capacity (8–10 wt%), insufficient pharmacokinetic and protein corona characterization under clinically relevant conditions, the absence of systematic zinc ion clearance data, and the lack of GMP-compatible synthesis protocols. The Design Triangle framework supports a pragmatic, stepwise translational pathway in which each design axis is independently validated before the advancement of combinatorial systems, with PEGylation and clinically established payloads (doxorubicin, methotrexate) identified as priority first-in-human candidates.