Phenylboronic Acid‐Modified Near‐Infrared Region II Excitation Donor–Acceptor–Donor Molecule for 2‐Deoxy‐d‐Glucose Improved Starvation/Chemo/Photothermal Combination Therapy

Synergistic chemotherapy and photothermal therapy (PTT) have emerged as a promising anticancer paradigm to achieve expected therapeutic effects while mitigating side effects. However, the chemo/PTT combination therapy suffers from limited penetration depth, thermoresistance performance of tumor cells, and low drug bioavailability. Herein, multifunctional nanoparticles (BTP/DOX/2DG NPs) coloaded with near‐infrared region II (NIR‐II) light excitation donor–acceptor–donor (D–A–D) small molecules, doxorubicin (DOX), and 2‐deoxy‐d‐glucose (2‐DG) are developed for reinforced starvation/chemo/NIR‐II PTT combination therapy. The synthesized phenylboronic acid (PBA)‐modified water‐soluble D–A–D molecule (BBT‐TF‐PBA) not only exhibits high binding ability to DOX and 2‐DG through donor–acceptor coordination interactions PBA–diol bonds but also serves as a photoactive agent for NIR‐II fluorescence imaging, NIR‐II photoacoustic imaging, and NIR‐II PTT. Under the acidic and oxidizing conditions in the tumor microenvironment, donor–acceptor coordination interactions and PBA–diol bond are decomposed, simultaneously releasing DOX and 2‐DG from BTP/DOX/2DG NPs to achieve effective chemotherapy and starvation therapy. 2‐DG also effectively inhibits the expression of heat shock protein and further enhances NIR‐II PTT and chemotherapy efficiency. In vitro and in vivo experiments demonstrate the combination effect of BTP/DOX/2DG NPs for chemotherapy, NIR‐II PTT, and starvation therapy. A novel multifunctional nanoparticle (BTP/DOX/2DG NP) capable of efficient near‐infrared II (NIR‐II) light excitation is reported, achieved through the coloading of phenylboronic acid‐modified water‐soluble donor–acceptor–donor small molecules BTP, doxorubicin, and 2‐deoxy‐d‐glucose into DSPE‐PEG2000 liposomes. It can serve as a phototherapeutic agent for NIR‐II fluorescence/NIR‐II photoacoustic imaging‐guided starvation/chemo/NIR‐II photothermal combination therapy in cancer.