To realize the therapeutic potential of gene drugs for Alzheimer’s disease (AD), non-invasive, tissue specific and efficient delivery technologies must be developed. Here, a hybrid system for amyloid plaques targeted siRNA delivery was formed by PEGylated Poly(2-(N,N-dimethylamino) ethyl methacrylate) (PEG-PDMAEMA) conjugated with two d-peptides, a CGN for brain penetration and a QSH for β-amyloid binding. The hybrid complex CQ/siRNA, composed of 25% MPEG-PDMAEMA, 50% CGN-PEGPDMAEMA and 25% QSH-PEG-PDMAEMA, showed negligible cytotoxicity and could protect siRNA from enzyme degradation. Being taken up by neuron cells, the complexes could escape from lysosomes, release siRNA in the cytoplasm and thus producing effective gene silence (down-regulated protein level to 18.5%). After intravenous injection, CQ/siRNA penetrated into the brain in an intact form and located around the plaques in transgenic AD mice. The precisely amyloid plaques delivery resulted in increased therapeutic activities, which was demonstrated by the strong mRNA (36.4%) knockdown of BACE1 (a therapeutic target of AD), the less yield of enzyme-digested products sAPPb (-42.6%), as well as the better neurons protection than the single component complexes. In conclusion, the hybrid complex could efficiently and precisely deliver an siRNA to the AD lesion and might be a potential candidate for gene therapy for AD.