pH-Responsive photothermal effect and heterojunction formation for tumor-specific pyroelectrodynamic and nanozyme-catalyzed starvation therapy

Pyroelectrodynamic therapy (PEDT) integrates photothermal ablation and catalytic generation of reactive oxygen species (ROS), yet tumor-specific PEDT remains unexplored. Herein, pyroelectric tetragonal BaTiO 3 (tBT) nanoparticles (NPs) were capped with polyaniline (PANI) via a Pickering emulsion-masking method, followed by in situ deposition of MnO 2 nanodots on PANI caps to synthesize Janus tBT@PANI-MnO 2 NPs. PANI emeraldine salts (PANI-ES) at pH 6.5 display strong near-infrared II (NIR-II) absorption and 4.67-fold higher photothermal conversion efficiency than that of PANI emeraldine base at pH 7.4. MnO 2 nanodots exhibit self-propagating glucose oxidase (GOx), peroxidase (POD), and catalase (CAT) catalytic activities, remodeling the tumor microenvironment and enhancing PTT and PEDT efficacy. Heterojunction formation with PANI-ES generates 1.63-fold higher pyroelectric potentials compared to pristine tBT NPs. The pyroelectric field selectively alters tumor cell membrane potential and, along with the self-propelled motion by asymmetrical thermophoresis from the Janus structure, promotes cellular uptake of NPs. Tumor accumulation of NPs increases 3.2 folds with broad intratumoral distributions of NPs and ROS. Synergistic toxicities to tumor cells arise from PANI-mediated photothermal effect, ROS generation from tBT-PANI heterojunctions, and MnO 2 nanozymes-catalyzed glucose depletion. Integration of PEDT, mild PTT and MnO 2 -catalyzed starvation therapy completely inhibits tumor growth, extends animal survival, elevated intratumoral O 2 levels, and suppressed adenosine triphosphate productions. Thus, this Janus NP design represents the first attempt to develop pH-responsive heterojunctions and enables tumor-specific PTT, PEDT and nanozyme-catalyzed starvation therapy. Statement of Significance Although phototherapy achieves light localization for tumor suppression, inevitable toxicities usually occur when light penetrates healthy tissues with accumulation of photoactive agents. Extensive efforts have been dedicated to exploring tumor microenvironment-responsive drug delivery systems, aiming to enhance tumor-targeting efficiency and treatment selectivity of anticancer agents. However, to date, no efforts have been made to develop a method that can achieve tumor-specific temperature elevation and pyroelectrodynamic therapy while simultaneously minimizing exposure to normal tissues. To address these challenges, a concise strategy is proposed to generate pyroelectric heterojunctions in response to the slightly acidic tumor microenvironment, taking advantages of reversible protonation and deprotonation properties of polyaniline. The tumor-specific conversion into polyaniline emeraldine salts triggers strong NIR-II absorptions and pyroelectric effect, and the self-propagated catalytic reactions of MnO 2 nanozymes reinforce photothermal, pyroelectrodynamic and starvation therapies of tumors.