Anti‐Quenching NIR‐II Excitation Phenylboronic Acid Modified Conjugated Polyelectrolyte for Intracellular Peroxynitrite‐Enhanced Chemo–Photothermal Therapy

Abstract Multidrug resistance to clinical chemotherapeutic drugs severely limits antitumor efficacy and patient survival. The integration of chemotherapy with photothermal therapy (PTT) and reactive nitrogen species has become a major strategy to enhance cancer treatment efficacy. Herein, a multifunctional peroxynitrite (ONOO − ) nanogenerator (PBT/NO/Pt) for NIR‐II fluorescence (NIR‐II FL)/NIR‐II photoacoustic (NIR‐II PA) imaging‐guided chemo/NIR‐II PTT/ONOO − combination therapy is reported. The multifunction nanogenerator is developed by co‐loading a pH‐sensitive nitric oxide donor (DETA NONOate) and nicotinamide adenine dinucleotide phosphate oxidases trigger superoxide (O 2 •− ) generator chemotherapy drug (CDDP) to an NIR‐II excitation‐conjugated polyelectrolyte (PNC11BA). PNC11BA has non‐conjugated alkyl chain segments in the polymer backbone and abundant positively charged phenylboronic acid in its side chains, which support the anti‐quenching of NIR‐II FL and the integration of DETA NONOate and CDDP into PBT/NO/Pt. In the acidic tumor microenvironment, the coordination bonds between CDDP and PNC11BA are cleaved, releasing CDDP for chemotherapeutic activity. The simultaneous release of nitric oxide (NO) and O 2 •− rapidly leads to the in situ generation of the more cytotoxic reactive physiological nitrogen species ONOO − . In vitro and in vivo results prove that PBT/NO/Pt exhibited a markedly ONOO − enhanced chemo–photothermal synergistic therapy for SKOV3/DDP tumor by downregulating the intracellular glutathione and increasing CDDP–DNA adducts.