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Organic-inorganic (O-I) nanomaterials are versatile platforms for an incredible high number of applications, ranging from heterogeneous catalysis, molecular sensing, cell targeting, imaging, cancer diagnosis and therapy, just to name a few. Much of their potential stems from the unique control of organic environments around inorganic sites within a single O-I nanomaterial, which allows for new properties inaccessible using purely organic or inorganic materials. Structural and mechanistic characterization plays a key role in understanding and rationally designing such hybrid nanoconstructs. Here, we introduce a general methodology to identify and classify local (supra)molecular environments in an archetypal class of O-I nanomaterials, i.e. self-assembled monolayer-protected gold nanoparticles (SAM-AuNPs). By using an atomistic machine-learning guided workflow based on the Smooth Overlap of Atomic Positions (SOAP) descriptor, we analyze a collection of chemically different SAM-AuNPs, and detect and compare local environments in a way that is agnostic and automated, i.e. with no need of a-priori information and minimal user intervention. In addition, the computational results coupled with experimental electron spin resonance measurements prove that is possible to have more than one local environment inside SAMs, being thickness of the organic shell and solvation primary factors in determining number and nature of multiple co-existing environments. These indications are extended to complex mixed hydrophilic-hydrophobic SAMs. This work demonstrates that it is possible to spot out and compare local molecular environments in SAM-AuNPs exploiting atomistic machine-learning approaches, establishes ground rules to control them, and holds the potential for rational design of O-I nanomaterials instructed from data.

Two clinically approved anticancer drugs targeting BRAF in melanoma patients - dabrafenib (DAB) and vemurafenib (VEM) - have been successfully encapsulated into nanomicelles formed upon self-assembly of an amphiphilic dendrimer AD based on two C18 aliphatic chains and a G2 PAMAM head. The process resulted in the formation of well-defined (∼10 nm) core-shell nanomicelles (NMs) with excellent encapsulation efficiency (∼70% for DAB and ∼60% for VEM) and good drug loading capacity (∼27% and ∼24% for DAB and VEM, respectively). Dynamic light scattering (DLS), transmission electron microscopy (TEM), small-angle x-ray scattering (SAXS), nuclear magnetic resonance (NMR), isothermal titration calorimetry (ITC), and molecular simulation (MS) experiments were used, respectively, to determine the size and structure of the empty and drug-loaded nanomicelles (DLNMs), along with the interactions between the NMs and their cargoes. The in vitro release data revealed profiles governed by Fickian diffusion; moreover, for both anticancer molecules, an acidic environment (pH = 5.0) facilitated drug release with respect to physiological pH conditions (pH = 7.4). Finally, both DAB- and VEM-loaded NMs elicited enhanced response with respect to free drug treatments in 4 different melanoma cell lines.

International audience; Azacalixphyrins are used as building blocks to elaborate nanostructures with different shapes depending on the nature of the N-substituents. In this work, the formation of nanoribbons from N-alkyl azacalixphyrin 4, and of nanodonuts from the N-aryl analogue 5, is presented and rationalized by molecular dynamics (MD) simulations. Indeed, MD revealed different modes of intermolecular interactions (defines as nodes-and-trails and nodes-and-thorns models) according to the nature of the N-substituents. Nanoribbons based on 4 results from the stackings of the azacalixphyrin cores along the vertical direction, generating the nodes, while the van der Waals interactions between the N-C8H17 aliphatic chains generates the trails among the nodes along the ribbon. On the other hand, azacalixphyrin 5 self-assemblies into a nanodonut shape, in which the macrocyclic cores (nodes) stack along the horizontal plane while the 3,4,5-trimethoxyphenyl groups (thorns) point along the vertical direction towards the solvent where they establish a network of pi-pi interactions among their aromatic portions and H-bond interactions among the CH3O-groups and the solvent molecules, respectively.

The coronavirus disease-2019 (COVID-19) pandemic, caused by the pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), started in China during late 2019 and swiftly spread worldwide. Since COVID-19 emergence, many therapeutic regimens have been relentlessly explored, and although two vaccines have just received emergency use authorization by different governmental agencies, antiviral therapeutics based neutralizing antibodies and small-drug inhibitors can still be vital viable options to prevent and treat SARS-CoV-2 infections. The viral spike glycoprotein (S-protein) is the key molecular player that promotes human host cellular invasion via recognition of and binding to the angiotensin-converting enzyme 2 gene (ACE2). In this work, we report the results obtained by mutating in silico the 18 ACE2 residues and the 14 S-protein receptor binding domain (S-RBDCoV-2) residues that contribute to the receptor/viral protein binding interface. Specifically, each wild-type protein-protein interface residue was replaced by a hydrophobic (isoleucine), polar (serine and threonine), charged (aspartic acid/glutamic acid and lysine/arginine), and bulky (tryptophan) residue, respectively, in order to study the different effects exerted by nature, shape, and dimensions of the mutant amino acids on the structure and strength of the resulting binding interface. The computational results were next validated a posteriori against the corresponding experimental data, yielding an overall agreement of 92%. Interestingly, a non-negligible number of mis-sense variations were predicted to enhance ACE2/S-RBDCoV-2 binding, including the variants Q24T, T27D/K/W, D30E, H34S7T/K, E35D, Q42K, L79I/W, R357K, and R393K on ACE2 and L455D/W, F456K/W, Q493K, N501T, and Y505W on S-RBDCoV-2, respectively.

International audience; The alarming and prevailing antibiotic resistance crisis urgently calls for innovative "outside of the box" antibacterial agents, which can differ substantially from conventional antibiotics. In this context, we have established antibacterial candidates based on dynamic supramolecular dendrimer nanosystems selfassembled with amphiphilic dendrimers composed of a long hydrophobic alkyl chain and a small hydrophilic poly(amidoamine) dendron bearing distinct terminal functionalities. Remarkably, the amphiphilic dendrimer with amine terminals exhibited strong antibacterial activity against both Gram-positive and Gram-negative as well as drug-resistant bacteria, and prevented biofilm formation. Multidisciplinary studies combining experimental approaches and computer modelling together demonstrate that the dendrimer interacts and binds via electrostatic interactions with the bacterial membrane, where it becomes enriched and then dynamically self-assembles into supramolecular nanoassemblies for stronger and multivalent interactions. These, in turn, rapidly promote the insertion of the hydrophobic dendrimer tail into the bacterial membrane thereby inducing bacterial cell lysis and constituting powerful antibacterial activity. Our study presents a novel concept for creating nanotechnology-based antibacterial candidates via dynamic self-assembly and offers a new perspective for combatting recalcitrant bacterial infection.

A series of novel σ1 receptor ligands with a 4-(2-aminoethyl)piperidine scaffold was prepared and biologically evaluated. The underlying concept of our project was the improvement of the lipophilic ligand efficiency of previously synthesized potent σ1 ligands. The key steps of the synthesis comprise the conjugate addition of phenylboronic acid at dihydropyridin-4(1H)-ones 7, homologation of the ketones 8 and introduction of diverse amino moieties and piperidine N-substituents. 1-Methylpiperidines showed particular high σ1 receptor affinity and selectivity over the σ2 subtype, whilst piperidines with a proton, a tosyl moiety or an ethyl moiety exhibited considerably lower σ1 affinity. Molecular dynamics simulations with per-residue binding free energy deconvolution demonstrated that different interactions of the basic piperidine-N-atom and its substituents (or the cyclohexane ring) with the lipophilic binding pocket consisting of Leu105, Thr181, Leu182, Ala185, Leu186, Thr202 and Tyr206 are responsible for the different σ1 receptor affinities. Recorded logD7.4 and calculated clogP values of 4a and 18a indicate low lipophilicity and thus high lipophilic ligand efficiency. Piperidine 4a inhibited the growth of human non-small cell lung cancer cells A427 to a similar extent as the σ1 antagonist haloperidol. 1-Methylpiperidines 20a, 21a and 22a showed stronger antiproliferative effects on androgen negative human prostate cancer cells DU145 than the σ1 ligands NE100 and S1RA.

Drug binding to human serum albumin (HSA) significantly affects in vivo drug transport and biological activity. To gain insight into the binding mechanism of the two B-Raf tyrosine kinase inhibitors dabrafenib and vemurafenib to HSA, in this work, we adopted a combined strategy based on fluorescence spectroscopy, isothermal titration calorimetry (ITC), circular dichroism (CD), and molecular simulations. Both anticancer drugs are found to bind spontaneously and with a 1:1 stoichiometry within the same binding pocket, located in Sudlow's site II (subdomain IIIA) of the protein with comparable affinity and without substantially perturbing the protein secondary structure. However, the nature of each drug-protein interactions is distinct: whereas the formation of the dabrafenib/HSA complex is more entropically driven, the formation of the alternative vemurafenib/HSA assembly is prevalently enthalpic in nature. Kinetic analysis also indicates that the association rate is similar for the two drugs, whereas the residence time of vemurafenib within the HSA binding pocket is somewhat higher than that determined for the alternative B-Raf inhibitor.

The ability to control the properties of monolayer protected gold nanoparticles (MPNPs) discloses unrevealed features stemming from collective properties of the ligands forming the monolayer and presents opportunities to design new materials. To date, the influence of ligand end-group size and capacity to form hydrogen bonds on structure and hydration of small MPNPs (

The breast cancer type 1 susceptibility protein (BRCA1) and its partner - the BRCA1-associated RING domain protein 1 (BARD1) - are key players in a plethora of fundamental biological functions including, among others, DNA repair, replication fork protection, cell cycle progression, telomere maintenance, chromatin remodeling, apoptosis and tumor suppression. However, mutations in their encoding genes transform them into dangerous threats, and substantially increase the risk of developing cancer and other malignancies during the lifetime of the affected individuals. Understanding how BRCA1 and BARD1 perform their biological activities therefore not only provides a powerful mean to prevent such fatal occurrences but can also pave the way to the development of new targeted therapeutics. Thus, through this review work we aim at presenting the major efforts focused on the functional characterization and structural insights of BRCA1 and BARD1, per se and in combination with all their principal mediators and regulators, and on the multifaceted roles these proteins play in the maintenance of human genome integrity.

Over the last 30 years, there has been a tremendous increase in research on the use of lipid nanoparticles in the production of nanocarriers for drug delivery and biomedical imaging. The attraction of lipid nanoparticles (LNPs) for therapeutic and diagnostic applications is based on their capacity to load therapeutic and diagnostic substances, preserve them from degradation, improve absorption and intracellular penetration of the carried entity, adjust pharmacokinetics, reduce systemic toxicity, and overcome physiological barriers, just to cite their main features. Moreover, by means of various surface alteration methodologies, surface engineering on LNPs can be used to achieve active drug targeting. These characteristics make LNPs really appealing for loading sparingly water-soluble medicines with low bioavailability, poor pharmacokinetics, or different negative side effects. As a consequence of the hydrophobic effect, the self-assembly of amphiphilic lipids can result into different thermodynamically stable and weakly water soluble structures, recognized as lyotropic liquid crystalline (LLC) systems (i.e., lamellar, hexagonal, or bicontinuous cubic phases). Among the extensive family of LNPs obtainable from these structures, in this chapter we will focus on recent achievements of cubosomes as drug delivery agents. Firstly presented by Larsson and coworkers, cubosomes are a particular kind of lipid nanovesicles (NVs) produced by dispersion of a bicontinuous cubic phase LLC in water, with size ranging from 100 to 300 nm. The lipophilic bicontinuous cubic phase in cubosomes is able to create a thermodynamically stable three-dimensional (3D) network that keeps separate two distinct continuous, but non intersecting, hydrophilic regions. As a result, both water insoluble and soluble compounds can be loaded into these structures, either dissolved within the lipophilic 3D structure or adsorbed inside the hydrophilic channel walls, respectively.

Gold nanoparticles (AuNPs) have found applications in biomedicine as diagnostic tools, but extensive research efforts have been also directed toward their development as more efficient drug delivery agents. The high specific surface area of AuNPs may provide dense loading of molecules like catechols (L-DOPA and dopamine) on nanosurfaces, enabling functionalization strategies for advancing conventional therapy and diagnostic approaches of neurodegenerative diseases. Despite numerous well-described procedures in the literature for preparation of different AuNPs, possible transformation and structural changes of surface functionalization agents have not been considered thoroughly. As a case in point, the catechols L-DOPA and dopamine were selected because of their susceptibility to oxidation, cyclization, and polymerization. To assess the fate of coating and functionalization agents during the preparation of AuNPs or interaction at the nano-bio interface, a combination of spectroscopy, light scattering, and microscopy techniques was used while structural information and reaction mechanism were obtained by NMR in combination with computational tools. The results revealed that the final form of catechol on the AuNP nanosurface depends on the molar ratio of Au used for AuNP preparation. A large molar excess of L-DOPA or dopamine is needed to prepare AuNPs funtionalized with fully reduced catechols. In the case of molar excess of Au, the oxidation of catechols to dopamine quinone and dopaquinone was promoted, and dopaquinone underwent intramolecular cyclization in which additional oxidation products, leukodopachrome, dopachrome, or its tautomer, were formed because of the larger intrinsic acidity of the more nucleophilic amino group in dopaquinone. MD simulations showed that, of the oxidation products, dopachrome had the highest affinity for binding to the AuNPs surface. The results highlight how a more versatile methodological approach, combining experimental and in silico techniques, allows more reliable characterization of binding events at the surface of AuNPs for possible applications in biomedicine.

The purpose of this work is to provide an in silico molecular rationale of the role eventually played by currently circulating mutations in the receptor binding domain of the SARS-CoV-2 spike protein (S-RBDCoV‑2) in evading the immune surveillance effects elicited by the two Eli Lilly LY-CoV555/bamlanivimab and LY-CoV016/etesevimab monoclonal antibodies. The main findings from this study show that, compared to the wild-type SARS-CoV-2 spike protein, mutations E484A/G/K/Q/R/V, Q493K/L/R, S494A/P/R, L452R and F490S are predicted to be markedly resistant to neutralization by LY-CoV555, while mutations K417E/N/T, D420A/G/N, N460I/K/S/T, T415P, and Y489C/S are predicted to confer LY-CoV016 escaping advantage to the viral protein. A challenge of our global in silico results against relevant experimental data resulted in an overall 90% agreement. Thus, the results presented provide a molecular-based rationale for all relative experimental findings, constitute a fast and reliable tool for identifying and prioritizing all present and newly reported circulating spike SARS-CoV-2 variants with respect to antibody neutralization, and yield substantial structural information for the development of next-generation vaccines and monoclonal antibodies more resilient to viral evolution.

The purpose of this work was to provide an in silico molecular rationale of the role eventually played by currently circulating S-RBDCoV-2 mutations in evading the immune surveillance effects elicited by the two Eli Lilly LY-CoV555/bamlanivimab and LY-CoV016/etesevimab monoclonal antibodies. The main findings from this study and shows that, compared to the wild-type SARS-CoV-2 spike protein, mutations E484A/G/K/Q/R/V, Q493K/L/R, S494A/P/R, L452R and F490S are predicted to be markedly resistant to neutralization by LY-CoV555, while mutations K417E/N/T, D420A/G/N, N460I/K/S/T, T415P, and Y489C/S are predicted to confer LY-CoV016 escaping advantage to the viral protein. A challenge of our global in silico results against the relevant experimental data resulted in an overall 90% agreement. This achievement not only constitutes a further, robust validation of our computer-based approach but also yields a molecular-based rationale for all relative experimental findings, and leads us to conclude that the current circulating SARS-CoV-2 and all possible emergent variants carrying these mutations in the spike protein can present new challenges for mAb-based therapies and ultimately threaten the fully-protective efficacy of currently available vaccines.

siRNAs are emerging as promising therapeutic agents due to their ability to inhibit specific genes in many diseases. However, these tools require specific vehicles in order to be safely delivered to the targeted site. Among different siRNA delivery systems, self-assembled nanomicelles based on amphiphilic cationic dendrons (ACDs) have recently outperformed nanovectors based on covalent carriers. This chapter describes how isothermal titration calorimetry (ITC) can be exploited as one of the best techniques to investigate the self-assembly process of ACDs. Specifically, ITC can provide, as such or via specific analysis methods, a full thermodynamic characterization of these nanomicelles, including their critical micellar concentration, micelle aggregation number, degree of counterion binding, Gibbs free energy of micellization, and its enthalpic and entropic components.

This chapter reviews the different techniques for analyzing the chemical-physical properties, transfection efficiency, cytotoxicity, and stability of covalent cationic dendrimers (CCDs) and self-assembled cationic dendrons (ACDs) for siRNA delivery in the presence and absence of their nucleic cargos. On the basis of the reported examples, a standard essential set of techniques is described for each step of a siRNA/nanovector (NV) complex characterization process: (1) analysis of the basic chemical-physical properties of the NV per se; (2) characterization of the morphology, size, strength, and stability of the siRNA/NV ensemble; (3) characterization and quantification of the cellular uptake and release of the siRNA fragment; (4) in vitro and (5) in vivo experiments for the evaluation of the corresponding gene silencing activity; and (6) assessment of the intrinsic toxicity of the NV and the siRNA/NV complex.

1,3-Dioxanes 1 and cyclohexanes 2 bearing a phenyl ring and an aminoethyl moiety in 1,3-relationship to each other represent highly potent σ

A great deal of scientific and economic efforts is currently being focused on nanotechnology, providing ample opportunity for scientific advances and new products for virtually all fields of application. However, substantial hurdles still remain on the road from the conception of a nanomaterial to its everyday use or, in case of nanomedicine, to its adoption in the clinical practice. Some of these include, for instance, (1) the need to bridge existing interdisciplinary gaps in order to exploit all different fields of knowledge in the effective and efficient design, development and testing of new nanomaterials; (2) the necessity to define appropriate standardized methodologies and procedures along the entire nanomaterial production chain (i.e., from cradle to grave), thereby contributing actively in closing the persistent nanomaterial regulatory gap; and (3) the urgency to raise awareness about risks and benefits associated with nanotechnology and nanomaterials both to policy makers and the general public. This chapter will try to briefly review all these points, with a specific eye on nanomaterials for biomedical applications (aka nanomedicines).

siRNAs are emerging as promising therapeutic agents due to their ability to inhibit specific genes in many diseases. However, these tools require specific vehicles in order to be safely delivered to the targeted site. Among different siRNA delivery systems, self-assembled nanomicelles based on amphiphilic cationic dendrons (ACDs) have recently outperformed nanovectors based on covalent carriers. This chapter describes how isothermal titration calorimetry (ITC) can be exploited as one of the best techniques to investigate the self-assembly process of ACDs. Specifically, ITC can provide, as such or via specific analysis methods, a full thermodynamic characterization of these nanomicelles, including their critical micellar concentration, micelle aggregation number, degree of counterion binding, Gibbs free energy of micellization, and its enthalpic and entropic components.

1,3-Dioxanes 1 and cyclohexanes 2 bearing a phenyl ring and an aminoethyl moiety in 1,3-relationship to each other represent highly potent σ1 receptor antagonists. In order to increase the chemical stability of the acetalic 1,3-dioxanes 1 and the polarity of the cyclohexanes 2, tetrahydropyran derivatives 3 equipped with the same substituents were designed, synthesized and pharmacologically evaluated. The key step of the synthesis was a lipase-catalyzed enantioselective acetylation of the alcohol (R)-5 leading finally to enantiomerically pure test compounds 3a-g. With respect to σ1 receptor affinity and selectivity over a broad range of related (σ2, PCP binding site) and further targets, the enantiomeric benzylamines 3a and cyclohexylmethylamines 3b represent the most promising drug candidates of this series. However, the eudismic ratio for σ1 binding is only in the range of 2.5–3.3. Classical molecular dynamics (MD) simulations confirmed the same binding pose for both the tetrahydropyran 3 and cyclohexane derivatives 2 at the σ1 receptor, according to which: i) the protonated amino moiety of (2S,6R)-3a engages the same key polar interactions with Glu172 (ionic) and Phe107 (π-cation), ii) the lipophilic parts of (2S,6R)-3a are hosted in three hydrophobic regions of the σ1 receptor, and iii) the O-atom of the tetrahydropyran derivatives 3 does not show a relevant interaction with the σ1 receptor. Further in silico evidences obtained by the application of free energy perturbation and steered MD techniques fully supported the experimentally observed difference in receptor/ligand affinities. Tetrahydropyrans 3 require a lower dissociative force peak than cyclohexane analogs 2. Enantiomeric benzylamines 3a and cyclohexylmethylamines 3b were able to inhibit the growth of the androgen negative human prostate cancer cell line DU145. The cyclohexylmethylamine (2S,6R)-3b showed the highest σ1 affinity (Ki(σ1) = 0.95 nM) and the highest analgesic activity in vivo (67%).

Nowadays, computer simulations have been established as a fundamental tool in the design and development of new dendrimer-based nanocarriers for drug and gene delivery. Moreover, the level of detail contained in the information that can be gathered by performing atomistic-scale simulations cannot be obtained with any other available experimental technique. In this chapter we describe the main computational toolbox that can be exploited in the different stages of novel dendritic nanocarrier production-from the initial conception to the stage of biological intermolecular interactions.

Gene therapy using small interfering RNA (siRNA) is emerging as a novel therapeutic approach to treat various diseases. However, safe and efficient siRNA delivery still constitutes the major obstacle for clinical implementation of siRNA therapeutics. Here we report an ionizable supramolecular dendrimer vector, formed via self-assembly of a small amphiphilic dendrimer, as an effective siRNA delivery system with a favorable safety profile. By virtue of the ionizable tertiary amine terminals, the supramolecular dendrimer has a low positively charged surface potential and no notable cytotoxicity at physiological pH. Nonetheless, this ionizable feature imparted sufficient surface charge to the supramolecular dendrimer to enable formation of a stable complex with siRNA via electrostatic interactions. The resulting siRNA/dendrimer delivery system had a surface charge that was neither neutral, thus avoiding aggregation, nor too high, thus avoiding cytotoxicity, but was sufficient for favorable cellular uptake and endosomal release of the siRNA. When tested in different cancer cell lines and patient-derived cancer organoids, this dendrimer-mediated siRNA delivery system effectively silenced the oncogenes Myc and Akt2 with a potent antiproliferative effect, outperforming the gold standard vector, Lipofectamine 2000. Therefore, this ionizable supramolecular dendrimer represents a promising vector for siRNA delivery. The concept of supramolecular dendrimer nanovectors via self-assembly is new, yet easy to implement in practice, offering a new perspective for supramolecular chemistry in biomedical applications. [Figure not available: see fulltext.]

The recent emergence of the pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent for the coronavirus disease 2019 (COVID-19), is causing a global pandemic that poses enormous challenges to global public health and economies. SARS-CoV-2 host cell entry is mediated by the interaction of the viral transmembrane spike glycoprotein (S-protein) with the angiotensin-converting enzyme 2 gene (ACE2), an essential counter-regulatory carboxypeptidase of the renin-angiotensin hormone system that is a critical regulator of blood volume, systemic vascular resistance, and thus cardiovascular homeostasis. Accordingly, this work reports an atomistic-based, reliable in silico structural and energetic framework of the interactions between the receptor-binding domain of the SARS-CoV-2 S-protein and its host cellular receptor ACE2 that provides qualitative and quantitative insights into the main molecular determinants in virus/receptor recognition. In particular, residues D38, K31, E37, K353, and Y41 on ACE2 and Q498, T500, and R403 on the SARS-CoV-2 S-protein receptor-binding domain are determined as true hot spots, contributing to shaping and determining the stability of the relevant protein-protein interface. Overall, these results could be used to estimate the binding affinity of the viral protein to different allelic variants of ACE2 receptors discovered in COVID-19 patients and for the effective structure-based design and development of neutralizing antibodies, vaccines, and protein/protein inhibitors against this terrible new coronavirus.

The maintenance of genome integrity is essential for any organism survival and for the inheritance of traits to offspring. To the purpose, cells have developed a complex DNA repair system to defend the genetic information against both endogenous and exogenous sources of damage. Accordingly, multiple repair pathways can be aroused from the diverse forms of DNA lesions, which can be effective per se or via crosstalk with others to complete the whole DNA repair process. Deficiencies in DNA healing resulting in faulty repair and/or prolonged DNA damage can lead to genes mutations, chromosome rearrangements, genomic instability, and finally carcinogenesis and/or cancer progression. Although it might seem paradoxical, at the same time such defects in DNA repair pathways may have therapeutic implications for potential clinical practice. Here we provide an overview of the main DNA repair pathways, with special focus on the role played by homologous repair and the RAD51 recombinase protein in the cellular DNA damage response. We next discuss the recombinase structure and function per se and in combination with all its principal mediators and regulators. Finally, we conclude with an analysis of the manifold roles that RAD51 plays in carcinogenesis, cancer progression and anticancer drug resistance, and conclude this work with a survey of the most promising therapeutic strategies aimed at targeting RAD51 in experimental oncology.

Biology is dominated by polyanions (cell membranes, nucleic acids, and polysaccharides just to name a few), and achieving selective recognition between biological polyanions and synthetic systems currently constitutes a major challenge in many biomedical applications, nanovectors-assisted gene delivery being a prime example. This review work summarizes some of our recent efforts in this field; in particular, by using a combined experimental/computation approach, we investigated in detail some critical aspects in self-assembled nanomicelles and two major polyanions—DNA and heparin.

One of the major goals of computational materials science is the rapid and accurate prediction of properties of new materials. In order to design new materials and compositions for specific, high-performance applications, it is essential to rely on predictive tools for the estimation of the desired properties before material preparation, characterization and processing. In the future, new materials and systems will be characterized by progressively higher degrees of complexity, due to the strong relationship between nanotechnology, biotechnology, computer science and cognitive disciplines. However, computer power and simulation algorithms are also quickly evolving, opening new avenues for novel material and system design based on virtual (aka in silico) experiments. Notwithstanding the great advances achieved in the simulation of structural, thermal, mechanical and transport properties of materials at the macroscopic level, the accurate property prediction for complex nanostructured materials remains a critical issue in the material design strategy. This hurdle arises from the strong dependence of the material properties on the underlying nanostructure. Atomistic simulations based on molecular dynamics or Monte Carlo methods allow such structure–property relationships to be derived already for systems of noticeable size and time scales; yet, the study of highly complex systems (e.g., polymer nanocomposites and self-assembled nanomaterials) is still out of current reach at such a fine level of detail. Indeed, the fast advancement of high-performance computing has already expanded these time/scale windows, and the upcoming advent of hexascale and/or quantum-based computers will indeed further contribute to this expansion; yet, the investigation of many critical phenomena will remain inaccessible to atomistic-based simulations. To circumvent this limitation, multiscale simulation techniques have been developed to create a seamless bridge across different time/scale domains (from electronic to continuum methods), thereby providing reliable predictive tools to design engineers. Accordingly, in this review work we present a selection of case studies based on our own experience in multiscale molecular modeling of nanostructured, complex systems of industrial interest. The main goal of this objective is to show how multiscale in silico experiments in molecular systems design and engineering is at the same time theoretically sound and mature enough for its full exploitation.

International audience; Bioimaging has revolutionized medicine by providing accurate information for disease diagnosis and treatment. Nanotechnology‐based bioimaging is expected to further improve imaging sensitivity and specificity. In this context, supramolecular nanosystems based on self‐assembly of amphiphilic dendrimers for single photon emission computed tomography (SPECT) bioimaging are developed. These dendrimers bear multiple In3+ radionuclides at their terminals as SPECT reporters. By replacing the macrocyclic 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid cage with the smaller 1,4,7‐triazacyclononane‐1,4,7‐triacetic acid scaffold as the In3+ chelator, the corresponding dendrimer exhibits neutral In3+‐complex terminals in place of negatively charged In3+‐complex terminals. This negative‐to‐neutral surface charge alteration completely reverses the zeta‐potential of the nanosystems from negative to positive. As a consequence, the resulting SPECT nanoprobe generates a highly sought‐after biodistribution profile accompanied by a drastically reduced uptake in liver, leading to significantly improved tumor imaging. This finding contrasts with current literature reporting that positively charged nanoparticles have preferential accumulation in the liver. As such, this study provides new perspectives for improving the biodistribution of positively charged nanosystems for biomedical applications.

The sensing of small molecules poses the challenge to develop devices able to discriminate between compounds that may be structurally very similar. Here, attention has been paid to the use of self-assembled monolayer (SAM)-protected gold nanoparticles since they enable a modular approach to tune single-molecule affinity and selectivity simply by changing functional moieties (i.e. covering ligands), alongside with multivalent molecular recognition. To date, the discovery of monolayers suitable for a specific molecular target relies on trial-and-error approaches, with ligand chemistry being the main criteria used to modulate selectivity and sensitivity. By using molecular dynamics, we showcase that either individual molecular characteristics and/or collective features such as ligand flexibility, monolayer organization, ligand local ordering, and interfacial solvent properties can also be exploited conveniently. The knowledge of the molecular mechanisms that drive the recognition of small molecules on SAM covered nanoparticles will critically expand our ability to manipulate and control such supramolecular systems.

Breast cancer (BC) is the second leading cause of mortality in females after lung malignant neoplasms. Dedicated, noninvasive diagnostic screening methods for early detection and surveillance (e.g., mammography/echography) have indeed increased the five-year relative survival rate of women with BC from 75% in the 1970s to 91% in the middle 2010s. Sadly, however, the same life expectation for BC patients diagnosed at late stages is still as low as 26%, the leading cause of related mortality being metastasis to lymph nodes, lung, liver, bone, and brain. Therefore, more efficacious BC treatments beyond the current standards of chemotherapy, radiation, and surgery - all of which may damage not only disease cells but also healthy tissuesdare heavily needed. Nanomedicine (NM) is a multidisciplinary arena aiming at the design, synthesis, characterization and application of materials and devices with nanoscale dimensions (1-100 nm). As a rapidly developing field, NM offers concrete opportunities in hu- man cancer theranostics since, contrarily to conventional drugs, nanobased platforms may be designed and tailored for, e.g., overcoming biological barriers, allowing for prolonged blood circulation time, simultaneously exploiting both active tumor targeting and enhanced permeability and retention (EPR) effects, efficient drug delivery, and reduced or eliminated side effects. Approximately 50 cancer NMs approved by the Food and Drug Administration (FDA) are available in the clinics [6,7] and, according to the National Institute of Health (NIH), 243 clinical trials involving NMs in cancer theranostics are currently ongoing. Of these NMs, this chapter will review those targeting BC, briefly discussing the advantages they offer and underlying the challenges this emerging trend in the medical field still must face in paving the road to fulfill the European Union “Beating cancer by 2030” promise.