Fluorinated and Iodinated Bottlebrush Polymers as an Efficient Platform for Oxygen-Enriched and Heavy-Atom-Mediated Photodynamic Therapy

Abstract Photodynamic therapy (PDT) is a noninvasive, spatiotemporally selective modality that affords rapid healing with negligible scarring, but its clinical efficacy is severely limited by tumor hypoxia and aggregation-induced quenching of photosensitizers. Perfluorocarbons possess excellent oxygen dissolution and transport capacities and have been widely employed to construct oxygen-enriched microenvironments. In addition, the heavy-atom effect enhances intersystem crossing by promoting spin-orbit coupling, thereby increasing singlet oxygen generation. Herein, we synthesized a series of amphiphilic bottlebrush polymers (BBPs) covalently grafted with porphyrin photosensitizers, featuring tunable fluorine-containing side chains and iodine functionalization. Distinct from conventional polymeric PDT systems that primarily serve as photosensitizer carriers, the BBP architecture provides a confined multifunctional microenvironment that simultaneously regulates photosensitizer aggregation, oxygen availability, and intersystem crossing. The strong steric repulsion between neighboring side chains prevents undesired photosensitizer aggregation and preserves their photoactivity, while the fluorine-rich domains and iodine substituents cooperatively promote singlet oxygen generation through oxygen enrichment and external heavy-atom effects, respectively. Consequently, polymer vesicles assembled from these fluorinated and iodinated BBPs exhibit significantly enhanced PDT efficacy. This work establishes a cooperative molecular-design strategy that integrates aggregation suppression, oxygen regulation, and heavy-atom-enhanced intersystem crossing within a single bottlebrush polymer platform for improved PDT.