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Multifunctional nanocarriers are increasingly promising for disease treatment aimed to regulate multiple pathological dysfunctions and overcome barriers in drug delivery. Here we develop a multifunctional nanocarrier for Alzheimer's disease (AD) treatment by achieving therapeutic gene and peptide co-delivery to brain based on PEGylated dendrigraft poly- l -lysines (DGLs) via systemic administration. The dendritic amine-rich structure of DGLs provides plenty reaction sites and positive charge for drug loading. Successful co-delivery of drugs overcoming the blood–brain barrier by brain-targeted ligand modification was demonstrated both in vitro and in vivo . The pharmacodynamics study of the system following multiple-dosing treatment was verified in transgenic AD mice. Down-regulation of the key enzyme in amyloid-β formation was achieved by delivering non-coding RNA plasmid. Simultaneous delivery of the therapeutic peptide into brain leads to reduction of neurofibrillary tangles. Meanwhile, memory loss rescue in AD mice was also observed. Taken together, the multifunctional nanocarrier provides an excellent drug co-delivery platform for brain diseases. [ABSTRACT FROM AUTHOR]