Rosmarinic Acid‐Crosslinked Supramolecular Nanoassembly with Self‐Regulated Photodynamic and Anti‐Metastasis Properties for Synergistic Photoimmunotherapy

• Published in: Small (Weinheim an der Bergstrasse, Germany) Germany), 2023-06, Vol.19 (23), p.e2300594-n/a
• Main Authors: Zhou, Yang, Zhang, Yiwei, Jiang, Chaoqing, Chen, Yuxiu, Tong, Fan, Yang, Xiaotong, Wang, Yazhen, Xia, Xue, Gao, Huile
• Format: Article
• Language: English
• Subjects: Acids; Cell death; Cell Line, Tumor; Cinnamates - pharmacology; Crosslinking; Cyclodextrins; Damage accumulation; Effectiveness; Hydrogen peroxide; Immunosuppression; Metastasis; Micelles; Nanoparticles; Nanotechnology; Photochemotherapy - methods; photodynamic therapy; Photosensitizing Agents - pharmacology; Photosensitizing Agents - therapeutic use; Phototherapy; Porphyrins - pharmacology; Radiation damage; Reactive Oxygen Species - metabolism; Rosmarinic Acid; self‐regulation and antimetastasis; shell‐crosslinked; supramolecular nanoassembly; Tumors
• ISSN: 1613-6810; 1613-6829
• DOI: 10.1002/smll.202300594

A primary concern about photodynamic therapy (PDT) is its inability to regulate the generation levels of reactive oxidative species (ROS) based on the complex microenvironment, resulting in the impairment toward normal tissues and immunosuppression. Besides, tumor metastasis also compromises PDT's efficacy and drives mortality. However, it is very challenging to achieve such two goals within one nanosystem. Here, the nanoassembly (CPR) with self‐regulated photodynamic and antimetastasis properties comprises three parts: chlorin e6‐conjugated β‐cyclodextrin (CD‐Ce6) acts as the main PDT agent and ferrocene (Fc)‐terminated phenylboronic acid‐containing conjugates entering into the cavity of CD‐Ce6, as well as rosmarinic acid (RA)–boronic acid crosslinked shell. Compared with non‐crosslinked counterpart, CPR displays better stability and enhanced tumor accumulation. Under laser irradiation, CPR generates plenty of ROS to damage tumor cells and induce immunogenic cell death. Mildly acidic TME partly cleaves the crosslinkers to dissociate antioxidant RAs from micelles, which together with Fc in CPR scavenge PDT‐induced ROS in the TME. By contrast, under acidic lysosomal conditions, Fc catalyzes abundant H2O2 in tumor cells to produce highly cytotoxic •OH, while RA continuously reduces ferroptosis‐generated Fc+ into Fc, both to augment the PDT efficacy in tumor cells. CPR also remarkably hinders the epithelial‐mesenchymal transition to prevent the lung metastasis. A versatile supramolecular nanoassembly with rosmarinic acid‐crosslinked shell is employed, as the shell endows it with better stability and extended circulation, and it scavenges extracellular reactive oxidative species for reversal of immunosuppression, inhibits the epithelial‐mesenchymal transition, while in situ sustaining iron supply and, coupled with photodynamic therapy, promoting long‐lasting oxidative damage toward tumor and potent immunity.