Engineering Versatile Nanoparticles for Near-Infrared Light-Tunable Drug Release and Photothermal Degradation of Amyloid β

Nanomedicines that inhibit/disassemble amyloid β (Aβ) aggregates in Alzheimer's disease (AD) are highly desirable yet remain challenging. Therapeutic efficacy and systemic delivery of reported molecules and nanoparticles (NPs) are hampered by various challenges, including low biocompatibility, off-target toxicity, and lack of specificity. Herein, a versatile NP is designed by integrating high Aβ-binding affinity, stimuli-responsive drug release, and photothermal degradation properties for efficient disassembly of Aβ. Near-infrared (NIR)-absorbing conjugated polymer PDPP3T-O14 serves as a photothermal core while thermal-responsive polymer 1,2-dipalmitoyl-sn-glycero-3-phosphocholine at the outer layer as the NIR-stimuli gatekeeper. Curcumin, an inhibitor of Aβ aggregation, is loaded into the NP with high encapsulation efficiency. The 5-mer β-sheet breaker peptides LPFFD (Leu-Pro-Phe-Phe-Asp) having high binding affinity toward Aβ are further anchored onto the surface of polyethylene glycol-lipid shell for active Aβ-targeting. The resultant NPs exhibit good Aβ-targeting ability and obvious photothermal dissociation effect together with Aβ aggregation-dependent fluorescence detection capability. Upon NIR laser irradiation, entrapped curcumin can be effectively released from the unconsolidated NPs to enhance the anti-amyloid activity. In vitro studies demonstrate that the NPs dramatically lower Aβ-induced cytotoxicity of PC12 cells, and therefore show great potential for the application in AD treatment.