Multifunctional GM1–modified lipoprotein-like nanoparticles for the therapy of Alzheimer’s Disease Evaluation of: Huang M, Hu M, Song Q et al. GM1–modified lipoproteinlike nanoparticle: multifunctional nanoplatform for the combination therapy of Alzheimer’s disease. ACS Nano. 9(11), 10801–10816 (2015). Alzheimer’s disease (AD) is the most common neurodegenerative disorder, affecting about 11% of people aged 65 years and older in the USA alone. According to the estimates, this number may nearly triple by 2050 [1] resulting in an increased health and economic burden, which urgently calls for more effective therapies. The molecular basis for the formation of the extracellular amyloid plaques found in the brain of AD patients involves the strong neurotoxic effects of soluble amyloid-β (Aβ) [2]. In their recent paper, Huang et al. have developed a flexible multifunctional noninvasive drug delivery system for accelerated Aβ clearance, protection of neurons and inhibition of other pathological cascades induced by Aβ accumulation. Reconstituted high-density lipoprotein (rHDL) and monosialotetrahexosylganglioside (GM1)-rHDL nanoparticles were prepared by self-assembly from lipid-free apoE3 and 1,2–dimyristoyl-sn-glycero–3–phosphocholine (DMPC) liposomes or GM1–DMPC liposomes, respectively [3]. Surface plasmon resonance analysis showed a very high affinity of GM1–rHDL to monomeric and oligomeric Aβ 1–42 , comparable with anti-Aβ antibody binding. Following the extensive physicochemical analyses, in vivo experiments demonstrated a high level of GM1–rHDL in the brain after intranasal application in mice, confirming the feasibility of noninvasive administration of these nanoparticles. Subsequent in vitro and in vivo experiments revealed a strong improvement of different Aβ clearing pathways in the presence of GM1– rHDL as compared with rHDL. In primary microglia, GM1–rHDL facilitated the cellular uptake and intracellular degradation of Aβ 1–42 . Increased Aβ degradation and an accelerated Aβ brain-to-blood efflux after injection of I-labeled Aβ 1–42 oligomers into the unilateral hippocampus was also achieved in vivo with intranasally administered GM1–rHDL. Beside increased Aβ levels, AD is characterized by loss of neurons and synapses leading to memory loss, cognitive deficits and ultimately to death. Consequently, a successful therapy should combine strategies for Aβ clearance and neuroprotection. To verify the drugdelivery capacity of GM1–rHDL, the authors selected a neuroprotective octapeptide, NAP, as a model drug for AD. The resulting αNAP-GM1–rHDL particles increased the viability of Aβ 1–42 oligomer-treated primary neurons and reversed neuronal dysfunction by increasing the neurite length and branch point counts. Additionally, αNAP-GM1–rHDL Novel nanoparticulate drug delivery systems