Synergistic Engineering of pH-Responsive MSN@ZIF-8 Core–Shell Nanohybrids for Targeted Cancer Therapy: From Rational Design to Clinical Potential

This review critically examines the structural design and therapeutic mechanisms of hybrid nanocarriers combining mesoporous silica nanoparticles (MSNs) and Zeolitic Imidazolate Framework-8 (ZIF-8). While conventional chemotherapy is hindered by off-target toxicity and multidrug resistance, MSN@ZIF-8 hybrids offer a sophisticated solution by integrating the high cargo capacity of silica cores with the pH-gated degradability of ZIF-8 shells. Rather than a simple catalogue of recent studies, this article synthesizes the rational design logic behind solid versus hollow core architectures, elucidates the physicochemical principles of pH-triggered release, specifically the protonation of imidazole linkers, and analyzes the role of surface properties such as zeta potential, surface area, and wettability in cellular interaction. We highlight recent breakthroughs in co-delivery systems for chemotherapy, gene therapy, and theranostics, emphasizing the synergistic impact of Zn²⁺-mediated reactive oxygen species (ROS) generation. Finally, we move beyond general limitations to address specific translational barriers, including batch-to-batch reproducibility, scale-up of interfacial synthesis, and long-term formulation stability, proposing a roadmap for bridging the gap between benchtop innovation and clinical reality.