Functional covalent organic framework-based nanoagents for mitochondrial regulation related disease treatment

Abstract

Mitochondrial function and its regulation play a crucial role in the biomedical field. The occurrence and progression of many diseases, such as cancer and Alzheimer's disease (AD), are closely linked to mitochondrial dysfunction. In the ongoing search for disease diagnostic and therapeutic strategies, nanomedicine has flourished, and a range of nano biomaterials-based therapeutic drugs have been developed. Among these, covalent organic framework (COF) materials stand out as one of the most promising bio-medical nanomaterials due to their high crystallinity, ordered structure, intrinsic porosity, multifunctionality, and excellent biocompatibility. This thesis focuses on the synthesis of a series of COF-based composite nanomaterials at the nanoscale, with adjustments to their structure, size, and surface properties. The aim is to develop novel COF materials for mitochondrial regulation in the treatment of breast cancer and AD.
Firstly, three nanoscale imine-linked COFs, namely BTA-PPDA-COF, HBTA-PPDA-COF and TBTA-PPDA-COF have been successfully synthesized using a room-temperature synthesis approach. This method is environmentally friendly, versatile, and widely favored for its exceptional properties, including simplicity, ease of operation, and cost-effectiveness. Subsequently, the HBTA-PPDA-COF was functionalized in various ways to obtain two different nanoagents based on this COF, one is COF@PDA, and the other is D-/L-Cys-COF. These advancements highlight the potential of COF materials in the development of innovative and diverse therapeutic solutions.
Secondly, the self-polymerization of dopamine was applied for surface-modification of the COF, obtaining the COF@PDA nanoagent which had a core-shell structure and a size around 90 nm. The COF@PDA exhibited the ability to perform combined photodynamic/photothermal therapy for breast cancer, due to the multifunctional capability arising from the synergistic effects of the COF material and polydopamine (PDA). The COF took responsibility for producing abundant ROS to break redox homeostasis under 660 nm laser, in the meanwhile, the PDA exhibited an excellent photothermal ability under 808 nm light, resulting in joint inhibiting of tumor growth through the apoptosis pathway owing to its function of mitochondrial regulation. These results demonstrate that COF@PDA is a promising candidate for the intrinsic PDT/PTT combined treatment, along with the photo-induced mitochondrial regulation ability towards breast cancer. This dual therapeutic approach offers promising potential for more effective and precise treatment of breast cancer.
Thirdly, based on the D-/L-Cys-COF nanoagents, a chiral nanoparticle system was designed, and a strategy for AD treatment was proposed by restoring neuronal calcium homeostasis. Using a one-pot method, chiral cysteine functional components were integrated into the same COF’s skeleton, resulting in the construction of two chiral D-Cys-COF and L-Cys-COF nanoagents. The COF took the responsibility of the inhibition and disaggregation of Aβ42 fibrillization, and the Cys could normalize the cellular oxidative stress, further restored the NPY level as well as the calcium homeostasis of neuronal cells. At the cellular and animal levels, both D-Cys-COF and L-Cys-COF demonstrated excellent therapeutic efficacy for AD, but showed enantioselectively therapeutic effect, which could be attributed to the difference binding ability between cells and D-/L-Cys-COF.
In conclusion, this study developed a room-temperature synthesis method for COF nanomaterials and synthesized a variety of COF-based nanoplatforms using a series of functionalization techniques. These nanoagents were designed for the treatment of breast cancer and AD through mitochondrial regulation. This research provides new strategies and ideas for the design of nanomaterials related to mitochondrial regulation. The synthesized nanomaterials show promising application prospects in the field of biomedicine.

Date of Award	15 Nov 2025
Original language	English
Awarding Institution	University of Nottingham
Supervisor	Bencan Tang (Supervisor), Cheng Heng Pang (Supervisor), Moses Solomon (Supervisor) & Juan Li (Supervisor)