Activatable Immunotheranostic Nanovesicles for Coordinated Phagocytic Reprogramming and Real-Time Immune Monitoring

Abstract Cancer immunotherapy has revolutionized oncology, yet its efficacy against solid tumors remains severely hampered by the functional impairment and phenotypic skewing of immune cells within the tumor microenvironment. Here, we report a multifunctional nanoplatform that integrates potent immune reprogramming with real-time immune monitoring to enable both precise immunomodulation and dynamic assessment. We engineer genetically modified cell-derived nanovesicles codisplaying anti-CD47 nanobodies and calreticulin (CRT) signals to simultaneously block the CD47–SIRPα “don’t eat me” axis and deliver potent “eat me” cues, thereby promoting tumor cell phagocytosis and dendritic cell (DC) maturation. These nanovesicles, cloaked in a pH-responsive tannic acid–manganese (TA–Mn) shell, achieve systemic stability while enabling tumor-selective ligand exposure and Mn2+-mediated activation of the cGAS–STING pathway, further amplifying innate immune signaling. This coordinated modulation drives DC activation, augments antigen cross-presentation, and reprograms tumor-associated macrophages toward an M1 phenotype, eliciting robust CD8+ T cell responses and durable immunological memory. To enable spatiotemporal tracking of immune dynamics, the platform integrates a nitric oxide-activatable photoacoustic probe for in situ visualization of macrophage repolarization during therapy. Across multiple murine tumor models, this strategy eradicates established tumors, prevents metastasis, and confers long-term immune protection. Together, this study introduces a versatile and adaptive immunotherapeutic paradigm that couples activatable theranostics with robust immune reprogramming, advancing a new frontier in precision cancer immunotherapy.