Photothermal Responsive Polymersomes: From Molecular Design to Bio-applications

Organic photothermal nanoparticles (OPTNs), which convert light energy into heat upon irradiation, have garnered significant attention for biomedical applications. The performance of OPTNs is governed by several key parameters, including particle size, morphology, and photothermal conversion efficiency. In this thesis, we designed and synthesized OPTNs with diverse morphologies and tailored functionalities, providing new insights into their rational design, structural optimization, and functionalization for enhanced photothermal performance. In Chapter 2, we present a novel strategy for the design of photothermal responsive polymersomes. A small molecule photothermal agent (PTA) with near-infrared (NIR)-activated photothermal properties was synthesized and employed as a functional component. The design strategy was validated through molecular simulations, confirming its feasibility. PTA moieties were incorporated into the hydrophobic segment of a poly(ethylene glycol)-block-poly(trimethylene carbonate) (PEG-b-PTMC) copolymer, where the carbonate monomers were side-chain functionalized with active ester groups. The resulting amphiphilic block copolymers (PEG44-PTA2) served as building blocks for the self-assembly of photothermal responsive polymersomes (PTA-Ps). These polymersomes not only retained the photothermal functionality of PTA but also demonstrated excellent cargo loading capacities. In addition, PTA-Ps demonstrated effective photothermal therapeutic activity against cancer cells, highlighting their potential for biomedical applications. In Chapter 3, we systematically investigate the influence of organic solvent and copolymer chemical composition on the self-assembly behavior and resulting morphologies. Specifically, we demonstrated that, compared to vesicular structures, bicontinuous nanospheres (BCNs) exhibit enhanced light absorption, resulting in a higher absorption coefficient and improved photothermal conversion efficiency. Unlike traditional molecular engineering approaches, this solvent-induced strategy provides a simpler and more accessible route for tuning morphology without the need for complex molecular design or synthesis, offering a practical alternative for the development of high-performance OPTNs. In Chapter 4, polymersomes with asymmetric morphology were successfully fabricated through a hierarchical liquid-liquid phase separation assembly process. To elucidate the formation mechanism of these polymersomes featuring surface-integrated nanoparticles, we conducted an in-depth investigation of the self-assembly pathway, focusing on the incorporation of PTA nanoparticles into the vesicle membrane. Liquid-phase transmission electron microscopy (LP-TEM), employed as an advanced morphological characterization tool, overcame limitations of conventional electron microscopy by enabling in situ observation of the dynamic self-assembly process. Complementary optical microscopy further revealed early-stage phase separation during self-assembly, supporting our hypothesis that the formation of polymersomes with surface-bound nanoparticles is governed by a hierarchical liquid-liquid phase separation between PTA molecules and the block copolymers. Theoretical simulations provided additional mechanistic insights. Together, these findings offer a comprehensive understanding of the formation process of asymmetric polymersomes with surface-integrated nanoparticles, advancing the rational design of complex nanostructures for functional applications. Based on the findings in Chapter 4, Chapter 5 presents a strategy for employing asymmetric polymersomes with dual fluorescent and photothermal functionalities. These particles demonstrated strong AIE fluorescence. Simultaneously, they retained efficient photothermal conversion capabilities. Owing to their anisotropic structure, PTA-AIEsomes also showed promise as light-driven nanomotors. This combination of imaging and therapeutic functionality highlights their potential as multifunctional nanoplatforms for applications in both diagnostics and photothermal therapy. In Chapter 6, we developed a multicompartment system consisting of microcapsules embedded with photothermally responsive compartments (PTA-Ps) that function as near-infrared (NIR)-triggered nano-reservoirs. Upon NIR laser irradiation, these nano-reservoirs accelerated the release of encapsulated small molecules and facilitated enzymatic reactions. By integrating the NIR-responsive nano-reservoirs into the microcapsule framework, we established a hierarchical architecture capable of responding to external light stimuli to mediate inter-compartmental communication. This system also enabled the modulation of biochemical processes by varying the ratios of artificial cell populations, demonstrating its potential as a programmable microsystem. To further enhance the thermoresponsive behavior of photothermal responsive polymersomes, Chapter 7 presents the design and synthesis of photo-thermal triblock copolymers incorporating a thermosensitive segment, poly (N-isopropylacrylamide) (PNIPAm). These triblock copolymers (PEG44-PNIPAm30-PTAn) were synthesized through a combination of reversible addition – fragmentation chain transfer (RAFT) polymerization and post-polymerization modification. Upon self-assembly, these copolymers formed photothermal responsive polymersomes. Under near-infrared (NIR) irradiation, the polymersomes underwent membrane morphological changes due to the phase transition of the PNIPAm block, yet maintained their overall structural integrity and size. This reflects a finely tuned balance between dynamic adaptability and structural stability. Future work will explore the NIR-triggered cargo release behavior of this system to evaluate its potential for controlled delivery applications. In summary, this thesis presents the development of OPTNs, beginning with the rational design and synthesis of functional molecules and progressing to the fabrication of polymeric nanoparticles with diverse architectures and advanced functionalities. The strategies and methodologies established throughout this work offer a broadly applicable and efficient approach for the design of photothermal responsive polymeric nanomaterials, with potential for a wide range of biomedical applications.