NIR‐II Photoacoustic Imaging‐Guided Oxygen Delivery and Controlled Release Improves Photodynamic Therapy for Hepatocellular Carcinoma

Abstract Hypoxia, a prominent hallmark of hepatocellular carcinoma (HCC), undermines curative outcomes, elevates recurrence rates, and fosters metastasis, particularly during photodynamic therapy (PDT) in clinical settings. Studies indicate that alleviating tumor hypoxia enhances PDT efficacy. However, persistent challenges, including suboptimal oxygen delivery efficiency and absence of real‐time feedback on blood oxygen fluctuations during PDT, considerably impede therapeutic efficacy in tumor treatment. This study addresses these issues using near‐infrared‐II (NIR‐II) photoacoustic (PA) imaging for tumor‐targeted oxygen delivery and controlled release. For this purpose, a biomimetic oxygen delivery system designated BLICP@O 2 is developed, which utilizes hybrid tumor cell membranes and thermosensitive liposomes as oxygen carriers, incorporating the NIR‐II dye IR1048, photosensitizer chlorin e6 (Ce6), and perfluorohexane. Upon sequential irradiation at 1064 and 690 nm, BLICP@O 2 exhibits significant photothermal and photodynamic effects. Photothermal heating triggers oxygen release, enhancing the photodynamic effect of Ce6. Blood oxygen changes during PDT are tracked by multispectral PA imaging. Enhanced PDT efficacy, mediated by hypoxia relief, is convincingly demonstrated both in vitro and in vivo. This work presents an imaging‐guided, dual‐wavelength programmed cascaded treatment strategy for tumor‐targeted oxygen delivery and controlled release, with real‐time efficacy monitoring using PA imaging, offering valuable insights for overcoming challenges in PDT‐based cancer therapy.