Work

Enhanced nuclear enrichment of chemotherapeutics by a biomimetic ZIF-8 nanosystem for multidrug-resistant cancer treatment

Year: 2025

Type: article

Abstract: The exclusion of chemo-drugs from their target sites, e.g. the nucleus, is a critical factor contributing to the failure of chemotherapy. Nanoparticle-based technology holds promise for specific delivery of chemo-drugs to nucleus. However, limited lysosomal escape, small size of nuclear pores and incapability of direct regulation of drug efflux-related transporters made great challenges for nanoparticles. Here, a zeolitic imidazolate framework-8 (ZIF-8)-based nanosystem was found able to disrupt lysosomes by the pH-responsiveness of ZIF-8 and mediate the nuclear entry of chemotherapeutics through promotion of their passive diffusion, resulting in the decrease of half maximal inhibitory concentration (IC50) by 3.4-fold compared to free drugs. The additional encapsulation of small interfering RNA (siRNA) to specifically silence multidrug resistance gene 1 (MDR1) for reduction of drug efflux further enhanced the chemotherapy of cancer with multidrug resistance (MDR) (IC50 reduced by 5.2-fold compared to free drugs). With a macrophage membrane biosurface coating onto the nanoparticles, targeted and potent synergistic chemo-gene therapy was achieved in mice bearing cancer with MDR. The unique function of promoting chemotherapeutic nuclear accumulation by ZIF-8-based nanoparticles to fight against MDR may deepen our understanding of the nano/bio-interactions and give novel insights into the design of smart bioresponsive nanosystems for advanced therapy.

Source: European Journal of Pharmaceutical Sciences

DOI: 10.1016/j.ejps.2025.107396