Advanced Delivery Systems for Non‐perturbative Monitoring Patient‐Specific Cancer‐Immune Dynamics for Precision Personalized Therapy

ABSTRACT The interplay between cancer and immunity plays a pivotal role in cancer progression and therapeutic responses. However, studying cancer‐immune interactions in animal models suffers from the limited immune relevance. Moreover, to achieve non‐perturbative monitoring of the cancer‐immune interplay presents significant challenges. Here, we demonstrate that a real‐time imaging platform centered on a multifunctional delivery vector with ideal biocompatibility enables the precise study of patient‐specific cancer‐immune dynamics by integrating autologous circulating malignant cells (CMCs) and immune cells. Employing a cancer targeting delivery vector decorated with two types of aptamers, we achieve efficient genome editing via a plasmid delivery system for MET knockout and perform in situ mRNA probing via a molecular beacon delivery system to monitor CMC‐immune cell interactions, simultaneously track apoptosis and necroptosis, and reveal the impact of MET knockout on immune evasion at single‐cell resolution. During the immune attack, edited CMCs undergo pronounced apoptosis, characterized by a marked increase in BIM mRNA, along with necroptosis, as evidenced by elevated RIPK3 mRNA. In contrast, unedited CMCs demonstrate significantly higher immune resistance. By leveraging this versatile delivery platform, our study enables a critical advance in precision personalized therapy by correlating therapeutic actions with cancer cell death mechanisms under immune attack.