Zwitterionic Polarization-Engineering Covalent Organic Frameworks for Targeted Ferroptosis-Synergistic Photothermal Immunotherapy.

Combining efficient photocatalytic activity with precise targeting is crucial for covalent organic framework (COF)-based nanomedicines to remodel the immunosuppressive microenvironment and sensitize "cold" tumors to immunotherapy. Herein, we constructed two isomorphic frameworks featuring distinct electronic topologies: a zwitterionic squaric acid (SA) COF with inherent electrostatic asymmetry, and a charge-neutral terephthaldehyde (TA) COF. The spatial divergence of ion centers in SA COF triggers intense molecular-level ionic displacement polarization, creating a robust internal electric field. Such unique field-effect regulation accelerates photogenerated charge separation for efficient superoxide anion production, enhances intersystem crossing for singlet oxygen generation, and promotes nonradiative energy relaxation for high-performance photothermal conversion under dual-wavelength irradiation. After PEGylation and iRGD modification, the formulated SA@PEG-iRGD exhibits excellent physiological stability and active deep tumor penetration. With near-infrared absorption, it enables high-contrast photoacoustic imaging for guided dual-wavelength (660/808 nm) phototherapy. This spatiotemporally controlled therapeutic cascade triggers lethal ferroptosis and precise photothermal ablation, potently activating immunogenic cell death. Combined with aPD-L1 therapy, it eliminates primary tumors, produces abscopal effects, and establishes immune memory against recurrence and metastasis. This study highlights the value of electronic structure engineering in COF-based precision nanomedicine.