Engineered GLP-1R-targeting nanoplatforms: multimodal therapeutics in human diseases
Juan Zeng, Xinxin Tang, Dalian Qin, Yuling Lü, Xiaogang Zhou, Feng Chi, Jianing Mi, Hudan Pan, Jianming Wu, Bin Huang, Anguo Wu
Abstract
Glucagon-like peptide-1 receptor (GLP-1R) is a versatile therapeutic target that regulates glucose homeostasis, cardiovascular function, neuroprotection, and immune responses. Native GLP-1 undergoes rapid enzymatic degradation, limiting its clinical utility. To overcome these challenges, engineered GLP-1 analogues and nanotechnology-enabled delivery systems have emerged. This review summarizes recent advances in GLP-1R-targeted nanoplatforms, including lipid nanoparticles, polymeric carriers, inorganic nanoparticles, and biomimetic scaffolds that improve peptide stability, prolong circulation half-life, and enable selective tissue targeting. Ligand engineering approaches, such as site-specific peptide conjugation and fatty acid modifications, enhance receptor affinity and targeting precision. Stimuli-responsive release strategies that respond to glucose levels, pH shifts, and redox conditions restrict drug activation to diseased microenvironments. Multifunctional theranostic constructs co-encapsulate imaging probes with therapeutics, permitting real-time monitoring of biodistribution and receptor engagement. We discuss key translational challenges, including scalable manufacturing processes, quality control of particle size, ligand density, and release kinetics, and long-term biosafety concerns associated with inorganic materials and immune activation. Variability in GLP-1R expression among patient populations influences delivery efficacy, motivating personalized strategies guided by artificial intelligence and digital twin modeling. Emerging applications in neurodegenerative disorders, oncology, cardiovascular disease and immunology demonstrate the expanding clinical potential of GLP-1R nanomedicines. By integrating insights from materials science, pharmacology and preclinical studies, this review provides a cohesive framework for the rational design, evaluation and clinical translation of next-generation GLP-1R-targeted nanotherapeutics. Future directions include integration with genomic profiling and real-time biosensors to optimize therapeutic outcomes. Collaboration among chemists, biologists and clinicians will be essential to realize their full potential.