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

Abstract 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 Ag ₂ Te quantum dots (QDs) for near‐infrared II (NIR‐II) imaging, forming βGlus‐R848/Ag ₂ Te nanoparticles (NPs). Upon oral administration, βGlus facilitates the selective uptake of NPs by intestinal MΦ (βGlus‐R848/Ag ₂ Te 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, Ag ₂ Te 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.