nanomaterials Article Studies on Aggregated Nanoparticles Steering during Deep Brain Membrane Crossing Ali Kafash Hoshiar 1, * , Shahriar Dadras Javan 2 , Tuan-Anh Le 3 , Mohammad Reza Hairi Yazdi 2 and Jungwon Yoon 3, *   Citation: Kafash Hoshiar, A.; Dadras Javan, S.; Le, T.-A.; Hairi Yazdi, M.R.; Yoon, J. Studies on Aggregated Nanoparticles Steering during Deep Brain Membrane Crossing. Nanomaterials 2021, 11, 2754. https:// doi.org/10.3390/nano11102754 Academic Editor: Camelia Bala Received: 20 August 2021 Accepted: 14 October 2021 Published: 17 October 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 School of Computer Science and Electronic Engineering, University of Essex, Colchester CO4 3SQ, UK 2 School of Mechanical Engineering, University of Tehran, Tehran 1439955961, Iran; shahriardadras@ut.ac.ir (S.D.J.); myazdi@ut.ac.ir (M.R.H.Y.) 3 School of Integrated Technology, Gwangju Institute of Science and Technology, 123 Cheomdangwagi-ro, Buk-gu, Gwangju 61005, Korea; tuananhle@gist.ac.kr * Correspondence: A.kafashhoshiar@Essex.ac.uk (A.K.H.); jyoon@gist.ac.kr (J.Y.); Tel.: +44-12-0687-2060 (A.K.H.); +82-62-715-5332 (J.Y.) Abstract: Many central nervous system (CNS) diseases, such as Alzheimer’s disease (AD), affect the deep brain region, which hinders their effective treatment. The hippocampus, a deep brain area critical for learning and memory, is especially vulnerable to damage during early stages of AD. Magnetic drug targeting has shown high potential in delivering drugs to a targeted disease site effectively by applying a strong electromagnetic force. This study illustrates a nanotechnology-based scheme for delivering magnetic nanoparticles (MNP) to the deep brain region. First, we developed a mathematical model and a molecular dynamic simulation to analyze membrane crossing, and to study the effects of particle size, aggregation, and crossing velocities. Then, using in vitro experiments, we studied effective parameters in aggregation. We have also studied the process and environmental parameters. We have demonstrated that aggregation size can be controlled when particles are subjected to external electromagnetic fields. Our simulations and experimental studies can be used for capturing MNPs in brain, the transport of particles across the intact BBB and deep region targeting. These results are in line with previous in vivo studies and establish an effective strategy for deep brain region targeting with drug loaded MNPs through the application of an external electromagnetic field. Keywords: Alzheimer’s disease; hippocampus; magnetic nanoparticles; electromagnetic actuation; swarm steering; nanorobotics 1. Introduction Alzheimer’s disease (AD) continues to be a growing public health concern. It is estimated that there will be over 115 million new worldwide cases of AD within the next 40 years, resulting in an overwhelming health and economic burden on society [1]. The cases where AD was determined as the cause of death have increased by 68% between 2000 and 2010 [2]. Given the major public health priority of AD, the Alzheimer’s Asso- ciation released the National Alzheimer’s Plan, From Act to Action, outlining a national strategy to address AD research, care, and services with the specific goal of finding effective ways to prevent and treat the disease by 2025. AD is characterized by progressive cognitive dysfunction often beginning with an early disturbance of episodic memory and ultimately leading to absolute functional impairment. The apparent pathological processes caused by AD include misprocessing of fibrillar amyloid leading to oligomerization, the deposition of amyloid plaque causing a disruption of neural network activity, a loss of synaptic function, and eventual neuronal death [3,4]. As AD patients are often resistant to pharmacotherapy, alternative therapeutic strategies are imperative. Nanomaterials 2021, 11, 2754. https://doi.org/10.3390/nano11102754 https://www.mdpi.com/journal/nanomaterials