Gene-triggered theranostics for T cell-mediated inflammatory disorders via a multifunctional nanomedicine

Aberrant activation and self-attacking are the key characterization of T cell-mediated inflammatory disorders. Early detection and effective intervention of pathogenic activated T cells may provide a better prognosis. To achieve this goal, we designed a multifunctional nanomedicine named BLDHs-pAP-1@HSVtk-Fluc (BLDHs-pA1@Hk-Fc), and tested its capacity for pathogenic activated T cell tracking and elimination in inflammatory disorders mice model, for instance, dextran sodium sulfate (DSS)-induced inflammatory bowel disease (IBD). Herein, BLDHs-pA1@Hk-Fc nanomedicine with an AP-1-responsive dual-response core that integrates optical tracking (firefly luciferase, F-luc) and targeted ablation (herpes simplex virus thymidine kinase, HSVtk) capabilities. Encapsulated within BSA (bovine serum albumin) engineered layered double hydroxides (LDHs), the plasmid coding with AP-1 promoter could be effectively delivered into T cells in vivo and specifically activated in CD4+/CD8+ T cells upon antigen stimulation, triggering a 51.7-fold increase in firefly luciferase bioluminescence. Upon systemic administration, BLDHs-pA1@Hk-Fc preferly accumulated in the inflammatory sites (1.28-fold healthy colon) in vivo, enabling noninvasive pathogenic T cell dynamics tracking via bioluminescence imaging. Furthermore, HSVtk-ganciclovir (GCV) suicide system could effectively eliminate pathogenic activated T cells and mitigate inflammation progression in IBD mice model. In conclusion, BLDHs-pA1@Hk-Fc potentially represents a novel paradigm for theranostics in T cell-mediated inflammatory disorders. Schematic illustration of BLDHs-pA1@Hk-Fcsynthesis and synchronous diagnosis-treatment mechanism for IBD. (A) The process of BLDHs-pA1@Hk-Fc preparation. (B) After intravenous injection of BLDHs-pA1@Hk-Fc, the AP-1 promoter-controlled F-luc and HSV tk dual reporter gene plasmid was delivered to lesion site, the pathogenic activated T cells was detected and eliminated via bioluminescence and HSV tk /GCV suicide system, respectively. Created with BioRender.com. • First AP-1-responsive nanotheranostic system enables simultaneous tracking and ablation of pathogenic T cells. • In vivo gene editing achieves 21.8× higher signal in activated vs. resting T cells. • Suicide gene system eliminates activated T cells with real-time therapeutic monitoring via optical imaging.