Amphiphilic Gold Nanoparticles: A Biomimetic Tool to Gain Mechanistic Insights into Peptide-Lipid Interactions

Abstract

Functional peptides are now widely used in a myriad of biomedical and clinical contexts, from cancer therapy and tumor targeting to the treatment of bacterial and viral infections. Underlying this diverse range of applications are the non-specific interactions that can occur between peptides and cell membranes, which, in many contexts, result in spontaneous internalization of the peptide within cells by avoiding energy‑driven endocytosis. For this to occur, the amphipathicity and surface structural flexibility of the peptides play a crucial role and can be regulated by the presence of specific molecular residues that give rise to precise molecular events. Nevertheless, most of the mechanistic details regulating the encounter between peptides and the membranes of bacterial or animal cells are still poorly understood, thus greatly limiting the biomimetic potential of these therapeutic molecules. In this arena, finely engineered nanomaterials—such as small amphiphilic gold nanoparticles (AuNPs) protected by a mixed thiol monolayer—can provide a powerful tool for mimicking and investigating the physicochemical processes underlying peptide-lipid interactions. Within this perspective, we present here a critical review of membrane effects induced by both amphiphilic AuNPs and well-known amphiphilic peptide families, such as cell-penetrating peptides and antimicrobial peptides. Our discussion is focused particularly on the effects provoked on widely studied model cell membranes, such as supported lipid bilayers and lipid vesicles. Remarkable similarities in the peptide or nanoparticle membrane behavior are critically analyzed. Overall, our work provides an overview of the use of amphiphilic AuNPs as a highly promising tailor-made model to decipher the molecular events behind non-specific peptide-lipid interactions and highlights the main affinities observed both theoretically and experimentally. The knowledge resulting from this biomimetic approach could pave the way for the design of synthetic peptides with tailored functionalities for next-generation biomedical applications, such as highly efficient intracellular delivery systems.

Behavior of Citrate-Capped Ultrasmall Gold Nanoparticles on a Supported Lipid Bilayer Interface at Atomic Resolution

“…The AuNP inclusion in the DPPC SLB distorted the membrane vertically (i.e., buckling) due to local interactions, and lipids begin to fill the space underneath the zone of buckling, causing a partial bulging effect on the membrane. Furthermore, there is potential for this buckling effect to cause membrane “scarring” or deformations. − Computationally, the formation of membrane pores onto free-floating membranes has been partially explored, while effects of distortions/scarring onto SLBs have not been thoroughly investigated. − However, similar interactions may cause these membrane changes, while differences in bending curvature between SLB and vesicle systems may affect overall membrane scarring or deforming behavior. − …”

Antimikrobiyal Peptitlere Yönelik Güncel Eğilimler; Nanotaşıyıcı Sistemeler ve Farmasötik Uygulamalar

“…Bu peptitler yaygın olarak +2 ila +11 arasında değişen, lizin ve arginin kalıntıları gibi katyonik moleküller olarak nitelendirilen pozitif net yüke sahiptir (Getahun vd., 2022). Bu moleküller genellikle peptit dizisinde valin, lösin, izolösin, alanin, metionin, fenilalanin, tirozin ve triptofan gibi önemli miktarda hidrofobik kalıntıya sahiptir (Canepa vd., 2022).…”

“…Bu fosfolipidler, fizyolojik pH'da membran net yüküne katkıda bulunur. Zwitteriyonik fosfolipidlere ek olarak, zar boyunca kolesterol moleküllerinin varlığı da membran akışkanlığında ve esnekliğinde azalmaya katkıda bulunabilir ve bu da genellikle AMP aktivitesini azaltabilir (Canepa vd., 2022). Bu nedenle, AMP'ler genellikle terapötik kullanımları için çekici bir özellik olan memeli hücreleri için toksik değildir (Browne vd., 2020).…”

Cholesterol‐Containing Liposomes Decorated With Au Nanoparticles as Minimal Tunable Fusion Machinery

“…[41][42][43] The latter include sub-5 nm gold NPs (AuNPs) protected by an amphiphilic thiol monolayer comprising the negatively charged 11-mercapto-1-undecanesulfonate (MUS) and the apolar 1-octanethiol (OT). [44,45] The amphiphilic MUS:OT surface functionalization is extremely promising for biomedical purposes, as it allows for spontaneous NP penetration into biomimetic lipid bilayers [46][47][48][49][50][51][52] and mammalian cells [53][54][55][56][57][58] in a nondestructive way and the possibility of conjugating drug cargoes for intracellular delivery. [44,58,59] More interestingly, MUS:OT AuNPs recently demonstrated to induce hemifusion between phosphatidylcholines (PC) vesicles [52] and enable Ca 2+ -triggered fusion of pure PC membranes [41] a peculiar effect that does not occur when neutral zwitterionic membranes come into contact with calcium alone.…”