Innate Immunity‐Guided Macrophage‐Homing Nanoplatform for Oral Tumor Immunotherapy and Real‐Time Deep‐Tissue Imaging in Pre‐Clinical Models

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with poor prognosis and a high propensity for liver metastasis. This study presents an innate immunity-guided, macrophage (MΦ)-homing nanoplatform that enables oral delivery of theranostic agents to PDAC lesions by harnessing the migratory behavior of endogenous MΦ toward tumor-derived immune cues. The nanoplatform integrates a βGlus-R848 prodrug-constructed by conjugating β-glucans (βGlus) with the immunomodulator resiquimod (R848) via a reactive oxygen species (ROS)-responsive thioketal linker-and Ag₂Te quantum dots (QDs) for near-infrared II (NIR-II) imaging, forming βGlus-R848/Ag₂Te nanoparticles (NPs). Upon oral administration, βGlus facilitates the selective uptake of NPs by intestinal MΦ (βGlus-R848/Ag₂Te NPs@MΦ), which subsequently migrate to the tumor microenvironment (TME). There, elevated ROS levels trigger the release of R848, reprogramming tumor-associated MΦ from an immunosuppressive M2 to an immunoactive M1 phenotype. This immune activation remodels the stroma, enhances T cell infiltration, and transforms the TME into an immunoactive state, thereby improving therapeutic outcomes. Concurrently, Ag₂Te QDs enable deep-tissue NIR-II imaging for real-time visualization of PDAC progression, liver metastasis, and treatment response. Guided by innate immune signals, this MΦ-homing theranostic platform offers a promising strategy to overcome current challenges in PDAC treatment by integrating targeted immunotherapy with noninvasive, real-time disease monitoring.