Polyamine-Depleting Hydrogen-Bond Organic Frameworks Unleash Dendritic Cell and T Cell Vigor for Targeted CRISPR/Cas-Assisted Cancer Immunotherapy.

Abstract

Polyamines have tantalized cancer researchers as a potential means to rein in the rampant growth of cancer cells. However, clinical trials in recent decades have disappointed in delivering notable progress. Herein, a microfluidic-assisted synthetic hydrogen-bond organic framework (HOF) as a polyamine-depleting nanoplatforms designed to unleash the vigor of both dendritic cells (DCs) and T cells for precision cancer immunotherapy is reported. Upon internalization by tumor cells, the loaded plasma amine oxidase (PAO) in HOF efficiently depletes polyamines, remolding the tumor microenvironment and alleviating T-cell immunosuppression. This process also generates acrolein and H₂O₂, triggering CRISPR-assisted neoantigen generation. Specifically, Acrolein induces carbonyl stress, increasing mutational burdens. Simultaneously, HOF leverages the energy from the bis[2,4,5-trichloro-6-(pentyloxycarbonyl)phenyl] oxalate (CPPO)-H₂O₂ reaction for CRET-triggered singlet oxygen production, leading to thioether bond cleavage and release CRISPR-Cas9. Once released, CRISPR-Cas9 knocks out the DNA mismatch repair (MMR)-related MLH1 gene, further elevating mutational burdens and generating neoantigens, ideal targets for DCs. This dual-action strategy not only corrects T-cell immunosuppression but also enhances DC efficacy, presenting a powerful approach for tumor immunotherapy.