Hypoxia-accelerating pyroptosis nanoinducers for promoting image-guided cancer immunotherapy

Abstract

Precise image-guided cancer immunotherapy holds immense potential in revolutionizing cancer treatment. The strategies facilitating activatable imaging and controlled therapeutics are highly desired yet to be developed. Herein, we report a new pyroptosis nanoinducer that integrates aggregation-induced emission luminogen (AIEgen) and DNA methyltransferase inhibitor with hypoxia-responsive covalent organic frameworks (COFs) for advanced image-guided cancer immunotherapy. We first synthesize and compare three donor-acceptor type AIEgens featuring varying numbers of electron-withdrawing units, and find that the incorporation of two acceptors yields the longest response wavelength and most effective photodynamic therapy (PDT) property, surpassing the performance of analogs with one or three acceptor groups. A COF-based nanoplatform containing AIEgen and pyroptosis drug is successfully constructed via the one-pot method. The intra-COF energy transfer significantly quenches AIEgen, in which both fluorescence and PDT properties greatly enhance upon hypoxia-triggered COF degradation. Moreover, the photodynamic process exacerbates hypoxia, accelerating pyroptosis drug release. The nanoagent enables sensitive delineation of tumor site through in situ activatable fluorescence signature. Thanks to the exceptional ROS production capabilities and hypoxia-accelerating drug release, the nanoagent not only inhibits primary tumor growth but also impedes the progression of distant tumors in 4T1 tumor-bearing mice through potent pyroptosis-mediated immune response. This research introduces a novel strategy for achieving activatable phototheranostics and self-accelerating drug release for synergetic cancer immunotherapy.

Keywords: Activatable probe; Aggregation-induced emission; Cancer immunotherapy; Photodynamic therapy; Pyroptosis.