**2. Interaction of Nanoparticles with Cell Membrane**

The shape and biological functions of membranes can be strongly influenced by attached, encapsulated (Figure 1) [30], or intercalated inclusions such as nanoparticles (NPs). Unique optical, electronic, catalytic, and magnetic properties of NPs make them very interesting for a variety of biomedical applications [1,31–34]. For example, functional NPs and quantum dots are potential candidates for drug delivery, as well as carriers for cancer therapy [33,35]. When NPs interact with cells, the first barrier that NPs encounter is the plasma membrane. Intra- and extracellular transport of NPs are possible by a dynamic membrane shape transformation that involves a change in the membrane curvature (encapsulation) [30,32,33,36] (Figure 1). Membrane deformations may progress passively, that is, without employing an additional energy source, driven solely by the interaction between the membrane and NPs. Viral budding comprises such an example [37]. The intracellular entry of genetic material is presently receiving considerable attention due to the COVID-19 crisis. Electrostatic interactions [38,39] may facilitate NP or virus internalization via encapsulation [30,33] (Figure 1). Understanding the interplay between the membrane elastic and electrostatic properties of the NP–membrane complex, toward the encapsulation of NPs by the cell membrane, is also relevant for cellular drug uptake, viral budding, biotechnological applications, and studying the interactions of inorganic NPs with biological membranes [32,33].

**Figure 1.** Encapsulation of a spherical charged particle macro-ion. Snapshots of representative configurations obtained from Monte Carlo simulations for different numbers of charged lipids (each having one unit charge) in the membrane: 15, 60, and 150 (from left to right). The right figure corresponds to the situation of nearly complete encapsulation of the macro-ion. The spherical particle carries 65 uniformly distributed, point-like cations of valence 2. Reprinted from [30] with permission of AIP Publishing.

Another possible interaction of NPs with the membrane is the attachment (adsorption) of the former on the membrane surface [34,38,40], encapsulation [30], or their intercalation in the membrane [41–43]. The resulting configuration could be driven by the NP shape, charge, size, and stiffness; it also depends on the nature of the NP–membrane interaction [30,34,38,39,41,44]. For example, hydrophobic or cationic NPs with diameters smaller than 5 nm can be successfully embedded within the membrane bilayer. On the other hand, anionic NPs of the same size or larger NPs can only interact with the outer surface of the membrane [45]. NPs interacting with membranes may induce lateral tension that results in pore formation, either transient or permanent; the pores are actually stabilized by NPs. Nanoparticles could also cluster within the membrane, and the resulting change in the membrane mechanics could significantly influence its biological function and could even result in membrane disruption [46]. Simulations demonstrated that the properties of both the membrane and the NPs are equally important in explaining the membrane uptake of the latter [30,41].
