摘要Alzheimer's disease is a neurodegenerative disease induced by multiple interconnected mechanisms.Peptide drug candidates with multi-modal efficacy generated from fusion strategy are suitable for addressing multi-facet pathology.However,clinical translation of peptide drugs is greatly hampered by their low permeability into brain.Herein,a hybrid peptide HNSS is generated by merging two therapeutic peptides(SS31 and S-14 G Humanin(HNG)),using a different approach from the classical shuttle-therapeutic peptide conjugate design.HNSS demonstrated increased bio-permeability,with a 2-fold improvement in brain distribution over HNG,thanks to its structure mimicking the design of signal peptide-derived cell-penetrating peptides.HNSS efficiently alleviated mitochondrial dysfunction through the combined effects of mitochondrial targeting,ROS scavenging and p-STAT3 activation.Meanwhile,HNSS with increased Aβ affinity greatly inhibited Aβ oligomerization/fibrillation,and interrupted Aβ interaction with neuron/microglia by reducing neuronal mitochondrial Aβ deposition and promoting microglial phagocytosis of Aβ.In 3× Tg-AD transgenic mice,HNSS treatment efficiently inhibited brain neuron loss and improved the cognitive performance.This work validates the rational fusion design-based strategy for bio-permeability improvement and efficacy amplification,providing a paradigm for developing therapeutic peptide candidates against neurodegenerative disease.