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/Ag₂Te/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.