Macrophage Exosome-Engineered Nanoplatform with pH-Responsive Ratiometric Photoacoustic and NIR-II Fluorescence Imaging for Guided Photothermal Immunotherapy of Hepatocellular Carcinoma

The effectiveness of immunotherapy for hepatocellular carcinoma (HCC) is severely compromised by an immunosuppressive tumor microenvironment (TME) dominated by M2-polarized tumor-associated macrophages (TAMs), coupled with a lack of reliable strategies for real-time treatment monitoring. To address this, we developed a pH-responsive nanoimmunomodulator derived from macrophage exosomes for spatiotemporal TAM reprogramming combined with second near-infrared (NIR-II) theranostics. Our nanoplatform (anti-CD47 conjugated Croc@DMPC/Ag 2 Te/exosome, termed aCD47-CATE) is functionalized with anti-CD47 antibodies to block the CD47-“don’t eat me” signal. For precise theranostics, it co-encapsulates silver telluride quantum dots for high-contrast NIR-II fluorescence imaging and croconaine J-aggregates that serve as efficient photothermal converters (emission >1100 nm) and acid-activated photoacoustic probes. The aCD47-CATE platform integrates acid-activated ratiometric photoacoustic imaging with NIR-II fluorescence for accurate tumor targeting and delineation. It effectively blocks CD47 to promote macrophage phagocytosis while exerting mild photothermal effects under NIR-II irradiation to induce immunogenic cell death. This combined action potently remodels the immunosuppressive TME, achieving significant antitumor efficacy. Transcriptomic profiling validated this mechanism, showing enhanced T-cell and macrophage activation alongside suppressed immunosuppressive signals. Collectively, aCD47-CATE represents a robust and multifaceted theranostic platform for image-guided photothermal immunotherapy in HCC. A biomimetic nanotheranostic platform is engineered from macrophage exosomes for hepatocellular carcinoma therapy. The nanoparticle enables deep-tissue tumor visualization through NIR-II fluorescence and pH-responsive photoacoustic imaging. This dual-modal imaging guides a pH-activated photothermal therapy which synergizes with CD47 blockade immunotherapy, leading to effective tumor microenvironment remodeling and potent antitumor efficacy. • Engineered exosome targets and remodels immunosuppressive HCC TME • Synergistic immunotherapy via CD7 blockade and mild NIR-II PTT • Dual NIR-II imaging (pH-ratiometric PA & FL) monitors treatment efficacy