Self-assembly Of Building Blocks Research Articles

Supramolecular assembly of isomeric SN-38 prodrugs regulated by conjugation sites.

Supramolecular polymers (SPs) are an emerging class of drug transporters employed to improve drug therapy. Through the rational design of self-assembling monomers, one can optimize the properties of the resulting supramolecular nanostructures, such as size, shape, surface chemistry, release, and, therefore, biological fates. This study highlights the design of isomeric SN38 prodrugs through the conjugation of hydrophilic oligo(ethylene glycol) (OEG) with hydroxyls at positions 10 and 20 on hydrophobic SN-38. Self-assembling prodrug (SAPD) isomers 10-OEG-SN38 and 20-OEG-SN38 can self-assemble into giant nanotubes and filamentous assemblies, respectively, via aromatic associations that dominate self-assembly. Our study reveales the influence of modification sites on the assembly behavior and ability of the SN38 SAPDs, as well as drug release and subsequent in vitro and in vivo antitumor effects. The SAPD modified at position 20 exhibits stronger π-π interactions among SN38 units, leading to more compact packing and enhanced assembly capability, whereas OEG at position 10 poses steric hindrance for aromatic associations. Importantly, owing to its higher chemical and supramolecular stability, 20-OEG-SN38 outperforms 10-OEG-SN38 and irinotecan, a clinically used prodrug of SN38, in a CT26 tumor model, demonstrating enhanced tumor growth inhibition and prolonged animal survival. This study presents a new strategy of using interactions among drug molecules as dominating features to create supramolecular assemblies. It also brings some insights into creating effective supramolecular drug assemblies via the engineering of self-assembling building blocks, which could contribute to the optimization of design principles for supramolecular drug delivery systems.

Advances in Nucleic Acid Research: Exploring the Potential of Oligonucleotides for Therapeutic Applications and Biological Studies.

In recent years, nucleic acids have emerged as powerful biomaterials, revolutionizing the field of biomedicine. This review explores the multifaceted applications of nucleic acids, focusing on their pivotal role in various biomedical applications. Nucleic acids, including deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), possess unique properties such as molecular recognition ability, programmability, and ease of synthesis, making them versatile tools in biosensing and for gene regulation, drug delivery, and targeted therapy. Their compatibility with chemical modifications enhances their binding affinity and resistance to degradation, elevating their effectiveness in targeted applications. Additionally, nucleic acids have found utility as self-assembling building blocks, leading to the creation of nanostructures whose high order underpins their enhanced biological stability and affects the cellular uptake efficiency. Furthermore, this review delves into the significant role of oligonucleotides (ODNs) as indispensable tools for biological studies and biomarker discovery. ODNs, short sequences of nucleic acids, have been instrumental in unraveling complex biological mechanisms. They serve as probes for studying gene expression, protein interactions, and cellular pathways, providing invaluable insights into fundamental biological processes. By examining the synergistic interplay between nucleic acids as powerful biomaterials and ODNs as indispensable tools for biological studies and biomarkers, this review highlights the transformative impact of these molecules on biomedical research. Their versatile applications not only deepen our understanding of biological systems but also are the driving force for innovation in diagnostics and therapeutics, ultimately advancing the field of biomedicine.

Self-assembled photonic cavities with atomic-scale confinement

Despite tremendous progress in research on self-assembled nanotechnological building blocks, such as macromolecules1, nanowires2 and two-dimensional materials3, synthetic self-assembly methods that bridge the nanoscopic to macroscopic dimensions remain unscalable and inferior to biological self-assembly. By contrast, planar semiconductor technology has had an immense technological impact, owing to its inherent scalability, yet it seems unable to reach the atomic dimensions enabled by self-assembly. Here, we use surface forces, including Casimir–van der Waals interactions4, to deterministically self-assemble and self-align suspended silicon nanostructures with void features well below the length scales possible with conventional lithography and etching5, despite using only conventional lithography and etching. The method is remarkably robust and the threshold for self-assembly depends monotonically on all the governing parameters across thousands of measured devices. We illustrate the potential of these concepts by fabricating nanostructures that are impossible to make with any other known method: waveguide-coupled high-Q silicon photonic cavities6,7 that confine telecom photons to 2 nm air gaps with an aspect ratio of 100, corresponding to mode volumes more than 100 times below the diffraction limit. Scanning transmission electron microscopy measurements confirm the ability to build devices with sub-nanometre dimensions. Our work constitutes the first steps towards a new generation of fabrication technology that combines the atomic dimensions enabled by self-assembly with the scalability of planar semiconductors.

A methodological approach by capillary electrophoresis coupled to mass spectrometry via electrospray interface for the characterization of short synthetic peptides towards the conception of self-assembled nanotheranostic agents

Nanostructures formed by the self-assembling peptide building blocks are attractive materials for the design of theranostic objects due to their intrinsic biocompatibility, accessible surface chemistry as well as cavitary morphology. Short peptide synthesis and modification are straightforward and give access to a great diversity of sequences, making them very versatile building blocks allowing for the design of thoroughly controlled self-assembled nanostructures. In this work, we developed a new CE-DAD-ESI-MS method to characterize short synthetic amphiphilic peptides in terms of exact sequence and purity level in the low 0.1 mg.mL−1 range, without sample treatment. This study was conducted using a model sequence, described to have pH sensitive self-assembling property. Peptide samples obtained from different synthesis processes (batch or flow, purified or not) were thus separated by capillary zone electrophoresis (CZE). The associated dual UV and MS detection mode allowed to evidence the exact sequence together with the presence of impurities, identified as truncated or non-deprotected sequences, and to quantify their relative proportion in the peptide mixture. Our results demonstrate that the developed CE-DAD-ESI-MS method could be directly applied to the characterization of crude synthetic peptide products, in parallel with the optimization of peptide synthetic pathway to obtain controlled sequences with high synthetic yield and purity, which is crucial for further design of robust peptide based self-assembled nanoarchitectures.

Self-Assembly of RGD-Functionalized Recombinant Spider Silk Protein into Microspheres in Physiological Buffer and in the Presence of Hyaluronic Acid.

Biomaterials made of self-assembling protein building blocks are widely explored for biomedical applications, for example, as drug carriers, tissue engineering scaffolds, and functionalized coatings. It has previously been shown that a recombinant spider silk protein functionalized with a cell binding motif from fibronectin, FN-4RepCT (FN-silk), self-assembles into fibrillar structures at interfaces, i.e., membranes, fibers, or foams at liquid/air interfaces, and fibrillar coatings at liquid/solid interfaces. Recently, we observed that FN-silk also assembles into microspheres in the bulk of a physiological buffer (PBS) solution. Herein, we investigate the self-assembly process of FN-silk into microspheres in the bulk and how its progression is affected by the presence of hyaluronic acid (HA), both in solution and in a cross-linked HA hydrogel. Moreover, we characterize the size, morphology, mesostructure, and protein secondary structure of the FN-silk microspheres prepared in PBS and HA. Finally, we examine how the FN-silk microspheres can be used to mediate cell adhesion and spreading of human mesenchymal stem cells (hMSCs) during cell culture. These investigations contribute to our fundamental understanding of the self-assembly of silk protein into materials and demonstrate the use of silk microspheres as additives for cell culture applications.

1,8-Dihydroxy Naphthalene-A New Building Block for the Self-Assembly with Boronic Acids and 4,4'-Bipyridine to Stable Host-Guest Complexes with Aromatic Hydrocarbons.

The new Lewis acid-base adducts of general formula X(nad)B←NC5H4-C5H4N→B(nad)X [nad = 1,8-O2C10H6, X = C6H5 (2c), 3,4,5-F3-C6H2 (2d)] were synthesized in high yields via reactions of 1,8-dihydroxy naphthalene [nadH2] and 4,4'-bipyridine with the aryl boronic acids C6H5B(OH)2 and 3,4,5-F3-C6H2B(OH)2, respectively, and structurally characterized by multi-nuclear NMR spectroscopy and SCXRD. Self-assembled H-shaped Lewis acid-base adduct 2d proved to be effective in forming thermally stable host-guest complexes, 2d × solvent, with aromatic hydrocarbon solvents such as benzene, toluene, mesitylene, aniline, and m-, p-, and o-xylene. Crystallographic analysis of these solvent adducts revealed host-guest interactions to primarily occur via π···π contacts between the 4,4'-bipyridyl linker and the aromatic solvents, resulting in the formation of 1:1 and 1:2 host-guest complexes. Thermogravimetric analysis of the isolated complexes 2d × solvent revealed their high thermal stability with peak temperatures associated with the loss of solvent ranging from 122 to 147 °C. 2d, when self-assembled in an equimolar mixture of m-, p-, and o-xylene (1:1:1), preferentially binds to o-xylene. Collectively, these results demonstrate the ability of 1,8-dihydroxy naphthalene to serve as an effective building block in the selective self-assembly to supramolecular aggregates through dative covalent N→B bonds.

Self-Assembly of Selenium-Doped Carbon Quantum Dots as Antioxidants for Hepatic Ischemia-Reperfusion Injury Management.

Hepatic ischemia-reperfusion injury (HIRI) is a critical complication after liver surgery that negatively affects surgical outcomes of patients with the end-stage liver-related disease. Reactive oxygen species (ROS) are responsible for the development of ischemia-reperfusion injury and eventually lead to hepatic dysfunction. Selenium-doped carbon quantum dots (Se-CQDs) with an excellent redox-responsive property can effectively scavenge ROS and protect cells from oxidation. However, the accumulation of Se-CQDs in the liver is extremely low. To address this concern, the fabrication of Se-CQDs-lecithin nanoparticles (Se-LEC NPs) is developed through self-assembly mainly driven by the noncovalent interactions. Lecithin acting as the self-assembly building block also makes a pivotal contribution to the therapeutic performance of Se-LEC NPs due to its capability to react with ROS. The fabricated Se-LEC NPs largely accumulate in the liver, effectively scavenge ROS and inhibit the release of inflammatory cytokines, thus exerting beneficial therapeutic efficacy on HIRI. This work may open a new avenue for the design of self-assembled Se-CQDs NPs for the treatment of HIRI and other ROS-related diseases.

2-Amino-5-methylene-pyrimidine-4,6-dione-based Janus G-C nucleobase as a versatile building block for self-assembly.

This communication reports a nature-inspired Janus G-C nucleobase featuring two recognition sites: DDA (G mimic) and DAA (C mimic), which is capable of forming a linear tape-like supramolecular polymer structure. As demonstrated herein, the amino group of this self-assembling system can be further modified to yield a highly stable quadruple H-bonding system as well as a masked self-assembling system cleavable upon exposure to light.

Molecular design principles of helical pyramidal chirality self-organized from achiral hexakis(alkyloxy)triphenylene

2,3,6,7,10,11-Hexakis(alkyloxy)triphenylene (HATn) containing n = 4 to 12 carbons in its alkyl groups, are a classic group of discotic molecules self-organizing columnar liquid crystals. The structure of the crystalline assemblies of these discotic molecules were neglected since they were invented 45 years ago. Recently, we discovered that the crystal state of HAT4 consists of a highly ordered 8/1 helical chiral pyramidal 3D self-organization. In this publication we report the structural analysis of all 3D self-organizations of HATn containing n = 4 to 12 carbons in their achiral alkyls. Unexpectedly, the highly ordered 8/1 helical chiral pyramidal crystalline columns assembled from the crown-conformation of HAT4 is encountered also in the crystalline periodic array of HAT5. HAT6 self-organizes a 5/1 helical chiral pyramidal 3D column. HAT7 to HAT10 maintain their crown conformation in their 3D supramolecular pyramidal columns. However, their 3D pyramidal assemblies exhibit a nonhelical criss-cross arrangement. HAT11 and HAT12 self-organize 3D nonhelical columns from criss-cross arrangements of disc-like conformers. The structures of all these 3D helical and nonhelical pyramidal as well as of nonhelical discotic columns were resolved for the first time at the molecular level by reconstruction of their oriented fiber X-ray diffractograms with the help of molecular models. These results demonstrate that a single self-assembling building block can self-organize either helical chiral pyramidal or nonhelical pyramidal or even nonhelical discotic assemblies via two of its constitutional isomers. This outcome prompts essential questions related to the current standing of helical self-organizations. The most important question is, why over the past many years the scientific community explored helical self-organizations derived from long alkyl groups when the ideal alkyls for this process seem to be short? A hypothetic explanation of the findings reported here and of their impact on the field of helical self-organizations is presented.

Updates in the Use of 3D Bioprinting in Biomedical Engineering for Clinical Application: A Review

Three-dimensional (3D) printing is one of the most well-liked new innovative and promising manufacturing techniques, which has demonstrated tremendous potential for the creation of biostructures in tissue engineering, particularly for bones, orthopaedic tissues, and related organs. 3D printing for the medical industry was considered a lofty pipe dream. Time and money, though, made it a reality. Today's 3D printing technology has a significant possibility to assist pharmaceutical and medical corporations in developing more specialised pharmaceuticals, enabling the quick creation of medical implants, and transforming how doctors and surgeons approach surgical planning. In today's practise of precision medicine and for individualised therapies, patient-specific anatomical models that are 3D printed are becoming increasingly helpful tools. In contrast to the conventional use of 3D printing to create cell-free scaffolds, 3D bioprinting requires various technical methods, such as biomimicry, autonomous self-assembly, and mini-tissue building blocks, to create 3D structures with mechanical and biological properties suitable for the deposition of living cells and the restoration of tissue and organ function. Cells, bioinks, and bioprinters are all necessary components of the bioprinting process, and each one of them has biological, technological, ethical, and cost- and clinically-effectiveness-related issues. As a result, there are several difficulties in integrating 3D bioprinting into widespread clinical practise. Currently, there are multiple applications for 3D bioprinting such as in surgery, cardiovascular system, musculoskeletal and even in drug screening. All of which will be discussed in this review.

Structural control of self-assembled peptide nanostructures to develop peptide vesicles for photodynamic therapy of cancer.

Vesicles such as liposomes, polymersomes, and exosomes have been widely used as drug delivery carriers; however, peptide vesicles (peptidesomes) despite their potential utility are far less well developed. Peptidesomes are distinctive because peptides play dual roles as a self-assembly building block and a bioactive functional unit. In order for peptidesomes to become successful nanodrugs, the issues related to differences in nanostructural properties between in vitro and in vivo conditions should be addressed. Here, we delineate a multivariate approach to feedback control the structures of peptide building blocks, nanoparticle size, drug loading process, nanoparticle aggregation, cytotoxicity, cell targeting capability, endosome disruption function, protease resistance, and in vivo performance, which eventually enabled the successful development of a highly efficacious peptidesome for in vivo cancer therapy. This study lays the groundwork for the successful in vivo translation of peptide nanodrugs.

Systematic Analysis of Self-Assembled Nanodielectric Architecture and Organization Effects on Organic Transistor Switching

The unconventional self-assembled nanodielectric (SAND) architecture is composed of solution-processed alternating inorganic (e.g., ZrOx and HfOx) and π-organic nanolayers (e.g., stilbazolium). As gate dielectrics, SANDs are compatible with a wide variety of organic and inorganic semiconductors and often impart superior thin-film transistor (TFT) performance in comparison to analogous inorganic-only dielectrics. The enhanced performance has been partly attributed to the interactions within the organic layers. To probe the role of the highly polarizable stilbazolium (Chr) organic layer in SAND structural organization and dielectric response, a saturated hydrocarbon chain-based self-assembling building block (Alk) was synthesized and incorporated in SAND structures. By using Chr and Alk in the different SAND organic layers, the effects of the Chr built-in dipole on bulk SAND structural and dielectric characteristics can be evaluated. The Zr-SAND structures are characterized by atomic force microscopy, X-ray reflectivity, metal-insulator-semiconductor electrical measurements, and pentacene-based organic TFTs. The layer identity and arrangement of the organic layers within the Zr-SAND structure are found to have a significant impact on the capacitor leakage current and pentacene transistor threshold voltage/turn-on voltage characteristics. Furthermore, significant cooperative interactions between adjacent Chr organic π-layers are important in enhancing these effects.

Dissipative self-assembly of a dual-responsive block copolymer driven by a chemical oscillator

HypothesisCoupling stimuli-responsive building blocks with an oscillating reaction is an effective strategy to realize and investigate dissipative self-assembly. More importantly, since there is usually more than one component of which concentration periodically changes in a chemical oscillator, it can be expected that this strategy has the advantage of achieving dissipative self-assembly of the building blocks with dual- or even multi-responsiveness. ExperimentsWe realized the dissipative self-assembly of a pH- and iodine-responsive block copolymer, poly(ethylene oxide)-b-poly(2-vinyl pyridine) (PEO-P2VP), by coupling it with the IO3--SO32--Fe(CN)62- (ISF) oscillator, and investigated its rhythmic self-assembly behavior. Furthermore, we proposed a mechanistic model to simulate the kinetics of the ISF oscillator coupling with different amounts of PEO-P2VP. FindingsRhythmic core-shell reversal of the polymer micelles formed by PEO-P2VP was found in the ISF oscillator. The mechanistic model we proposed successfully reproduced the experimental oscillation and provided some data on the kinetics of the dual responsive self-assembly of PEO-P2VP. This line of research provided an example of realizing dissipative self-assembly of dual-responsive building blocks, which was seldom reported previously. It once again suggested that coupling with a suitable chemical oscillator is a promising strategy to have an insight into the kinetics of stimuli-responsive self-assembly.

Ag9(1,2-BDT)6]3-: How Square-Pyramidal Building Blocks Self-Assemble into the Smallest Silver Nanocluster.

The emerging promise of few-atom metal catalysts has driven the need for developing metal nanoclusters (NCs) with ultrasmall core size. However, the preparation of metal NCs with single-digit metallic atoms and atomic precision is a major challenge for materials chemists, particularly for Ag, where the structure of such NCs remains unknown. In this study, we developed a shape-controlled synthesis strategy based on an isomeric dithiol ligand to yield the smallest crystallized Ag NC to date: [Ag9(1,2-BDT)6]3– (1,2-BDT = 1,2-benzenedithiolate). The NC’s crystal structure reveals the self-assembly of two Ag square pyramids through preferential pyramidal vertex sharing of a single metallic Ag atom, while all other Ag atoms are incorporated in a motif with thiolate ligands, resulting in an elongated body-centered Ag9 skeleton. Steric hindrance and arrangement of the dithiolated ligands on the surface favor the formation of an anisotropic shape. Time-dependent density functional theory based calculations reproduce the experimental optical absorption features and identify the molecular orbitals responsible for the electronic transitions. Our findings will open new avenues for the design of novel single-digit metal NCs with directional self-assembled building blocks.

Triazine-Based Janus G-C Nucleobase as a Building Block for Self-Assembly, Peptide Nucleic Acids, and Smart Polymers.

This communication reports on the utility of a triazine-based self-assembling system, reminiscent of a Janus G-C nucleobase, as a building block for developing (1) supramolecular polymers, (2) peptide nucleic acids (PNAs), and (3) smart polymers. The strategically positioned self-complementary triple H-bonding arrays DDA and AAD facilitate efficient self-assembly, leading to a linear supramolecular polymer.

Electric Field Modulated Peptide Nano-Assembly

Molecular self-assembly is an emerging and powerful tool in the synthesis of functional nanoscale structures as a bottom-up fabrication method. Among different self-assembling molecules, peptides are fascinating building blocks for the construction of supramolecular assemblies. The combination of facile chemical synthesis, flexibility in synthesis depending on the side-chain property, biocompatibility, and relative stability makes peptide a convenient building block for biological and bio-inspired self-assembly. Non-covalent interactions such as hydrophobic interaction, π- π stacking, van der Waals interaction and N and C terminal modifications have directed the self-assembly of peptides to supramolecular nanostructures. By mimicking the structures occurring in nature, peptide materials play a unique role in a new generation of hybrid materials. However, the challenge in this field is to control the self-assembly process in order to design a desirable structure at the nanometer scale in the correct orientation and configuration. Controlling the hierarchical organization of self-assembling peptides into nanostructures opens up the possibility of developing biocompatible functional nano materials for various applications. In this study, we focus on the fabrication of peptide nanomaterials formed by the self-assembly by employing electric field modulation. Self-assembly in the presence of external forces is an adaptive, directed organization of molecular components. While forces may be generated as a result of spontaneous interactions among components of a system, intervention with external forces can significantly alter the epitaxial growth of basic building blocks and stability of self-assembled architecture. Superimposing these intrinsic and extrinsic forces provide greater degrees of freedom to control the structure and function of self-assembling materials.

In situ formation of tetraphenylethylene nano-structures on microgels inside living cells via reduction-responsive self-assembly.

Controlling the assembly of synthetic molecules in living systems is of significance for their adaptive applications. However, it is difficult to achieve, especially for composite self-assemblies, due to the complexity and dynamic change of the intracellular environment, and there exist technical difficulties for the direct visualization of organic and polymer self-assemblies. Herein, we demonstrate a novel strategy for the in situ formation of self-assembled micro-nano composite structures in a cell milieu using reduction-responsive microgels (MGs) as a platform. The MGs were prepared by a templating and crosslinking method using a synthetic amphiphlic polymer as the basic material and porous CaCO3 microparticles as the template. The aggregation-induced emission (AIE) tetraphenylethylene moieties and reduction-labile disulfide bonds in the MGs were employed as the self-assembly building blocks and triggering sites for the intracellular self-assembly, respectively. In the presence of reductive agents such as glutathione, nano-spikes were gradually formed on the MGs. After the MGs were internalized by cells, the in situ formation of microgel/nano-spike composite structures was evidenced by the enhanced fluorescence intensity and was further confirmed by direct transmission electron microscopy observation. This work provides an effective strategy to cope with the challenging task of achieving and probing controlled self-assembly in a cell milieu, leading to new insights into investigating biological self-assembly and promoting the development of micro-/nanomaterials by learning from nature.

Nanomechanics of self-assembled DNA building blocks

DNA has become a powerful platform to design functional nanodevices. DNA nanodevices are often composed of self-assembled DNA building blocks that differ significantly from the structure of native DNA. In this study, we present Flow Force Microscopy as a massively parallel approach to study the nanomechanics of DNA self-assemblies on the single-molecular level. The high-throughput experiments performed in a simple microfluidic channel enable statistically meaningful studies with nanometer scale precision in a time frame of several minutes. A surprisingly high flexibility was observed for a typical construct used in DNA origami, reflected in a persistence length of 10.2 nm, a factor of five smaller than for native DNA. The enhanced flexibility is attributed to the discontinuous backbone of DNA self-assemblies that facilitate base pair opening by thermal fluctuations at the end of hybridized oligomers. We believe that the results will contribute to the fundamental understanding of DNA nanomechanics and help to improve the design of DNA nanodevices with applications in biological analysis and clinical research.

Flexible Alkyl Tails Help Shape Matching and Close Packing in Self-Assembly of Supramolecular Structure

Due to the flexibility and bowl-shaped cavity, C-alkylpyrogallol[4]arenes (PgCx, where x represents the length of alkyl chains) have garnered much attention over the past decade in supramolecular chemistry. Such cyclic polyphenolic compounds have been shown to be an excellent molecular building block for self-assembly of a variety of crystalline materials and have been applied in many frontier research areas ranging from ion transport to gas absorption/separation and biomedicine. In this work, we demonstrate that the long flexible alkyl tails play a critical role in the self-assembly of PgCx. It is found that they help the shape matching between the self-assembled building blocks and improve the packing density, thus promoting formation of an unprecedented “tails-driven” supramolecular structure. The successful demonstration of this work paves a new route to self-assembly materials by tuning the functional alkyl tails of the building blocks.

A Matter of Size and Placement: Varying the Patch Size of Anisotropic Patchy Colloids.

Non-spherical colloids provided with well-defined bonding sites—often referred to as patches—are increasingly attracting the attention of materials scientists due to their ability to spontaneously assemble into tunable surface structures. The emergence of two-dimensional patterns with well-defined architectures is often controlled by the properties of the self-assembling building blocks, which can be either colloidal particles at the nano- and micro-scale or even molecules and macromolecules. In particular, the interplay between the particle shape and the patch topology gives rise to a plethora of tilings, from close-packed to porous monolayers with pores of tunable shapes and sizes. The control over the resulting surface structures is provided by the directionality of the bonding mechanism, which mostly relies on the selective nature of the patches. In the present contribution, we investigate the effect of the patch size on the assembly of a class of anisotropic patchy colloids—namely, rhombic platelets with four identical patches placed in different arrangements along the particle edges. Larger patches are expected to enhance the bond flexibility, while simultaneously reducing the bond selectivity as the single bond per patch condition—which would guarantee a straightforward mapping between local bonding arrangements and long-range pattern formation—is not always enforced. We find that the non-trivial interplay between the patch size and the patch position can either promote a parallel particle arrangement with respect to a non-parallel bonding scenario or give rise to a variety a bonded patterns, which destroy the order of the tilings. We rationalize the occurrence of these two different regimes in terms of single versus multiple bonds between pairs of particles and/or patches.