Bionanoconjugates in Neurodegeneration: Peptide-Nanoparticle Alliances for Next-Generation Therapies.

The convergence of peptides and nanoparticles through bionanoconjugation has emerged as a transformative strategy to address the persistent challenges in treating neurodegenerative disorders. Peptides, particularly short sequences (< 45 amino acids), offer unique advantages as protein mimetics, including structural flexibility, target specificity and blood-brain barrier permeability. Their clinical translation is hindered by rapid enzymatic degradation, short half-life, and poor bioavailability. Conjugation with nanoparticles, overcomes these limitations by enhancing stability, prolonging circulation, and enabling precise targeting. Peptide-nanoparticle conjugates, including TAT-functionalized gold nanoparticles and RGD-decorated polymeric systems, have shown significant improvements in blood brain barrier penetration. These advancements are associated with a reduction in amyloid-beta aggregation and the inhibition of tau hyperphosphorylation in preclinical models. These hybrids leverage peptides dual roles as therapeutic agents and drug carriers, often exploiting receptor-mediated transport for brain delivery. This review critically evaluates covalent and noncovalent conjugation strategies, such as carbodiimide chemistry, ligand exchange, and click reactions, highlighting their impact on structural stability and bioactivity. We further discuss advances in peptide classes, including cell-penetrating peptides, nuclear localization signals, targeting peptides and bioactive peptides, emphasizing their applications in mitigating oxidative stress, neuroinflammation, and protein misfolding in neurodegenerative disorders. Despite promising preclinical outcomes, challenges such as scalability, immunogenicity, and heterogeneous blood brain barrier models remain barriers to clinical translation. This review outlines a strategy for enhancing peptide-NP conjugates as future neurotherapeutics by integrating existing methodologies, therapeutic results, and challenges. This underscores the importance of collaborative efforts across various disciplines to bridge the gap between advancements in nanotechnology and their clinical applications.