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

Abstract

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 H 2 O 2 , 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)‐H 2 O 2 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.