Microglia are essential for maintaining homeostasis and responding to pathological events in the central nervous system (CNS). Their dynamic and multidimensional states in different environments are pivotal factors in various CNS disorders. However, therapeutic modulation of microglial states is challenging due to the intricate balance these cells maintain in the CNS environment and the blood-brain barrier's restriction of drug delivery. Nanomedicine presents a promising avenue for addressing these challenges, offering a method for the targeted and efficient modulation of microglial states. This review covers the challenges faced in microglial therapeutic modulation and potential use of nanoparticle-based drug delivery systems. We provide an in-depth examination of nanoparticle applications for modulating microglial states in a range of CNS disorders, encompassing neurodegenerative and autoimmune diseases, infections, traumatic injuries, stroke, tumors, chronic pain, and psychiatric conditions. This review highlights the recent advancements and future prospects in nanomedicine for microglial modulation, paving the way for future research and clinical applications of therapeutic interventions in CNS disorders. 

Harnessing nanomedicine for modulating microglial states in the central nervous system disorders: Challenges and opportunities

Peptides and proteins have recently emerged as efficient therapeutic alternatives to conventional therapies. Although their advent a few decades back, extensive exploration of various ailments or disorders began recently. The drawbacks of current chemotherapies and irradiation treatments such as drug resistance and damage to healthy tissues have enabled the rise of the peptides as quest for better prospects. The chemical tunability and smaller size make them easy to design selectively for target tissues. Other remarkable properties include antifungal, antiviral, anti-inflammatory, protection from hemorrhage stroke, and as therapeutic agents for gastric disorders, Alzheimer's, and Parkinson's diseases. Despite these unmatched properties, their practical applicability is often hindered due to their weak susceptibility to enzymatic digestion, degradation in serum, metabolism in the liver, clearance by the kidney, and immunogenic reactions. There are several methods adapted in order to increase the half-life of peptides such as chemical modifications, fusing with Fc fragment, change in amino acid composition, and by using carrier-based delivery. Among these, nano-carrier-mediated encapsulation not only increases the half-life of the peptides in vivo but also it aids in the targeted delivery. They are also efficient in delivering the therapeutic molecules across the blood-brain barrier (BBB), despite its structural complexity. Here, in this review we tried to emphasize on the possible potentiality of metallic nanoparticles to be used as efficient peptide delivery system against brain tumor, and neurodegenerative disorders. Significance Statement In this review, we have emphasized the various therapeutic applications of peptides/proteins, including antimicrobial, anticancer, anti-inflammatory, and neurodegenerative diseases. We also focussed on the challenges these peptides face under physiological conditions after administration. We highlighted the importance and potentiality of metallic nanocarriers in the ability to cross the blood-brain barrier, increasing the stability and half-life of peptides, their efficiency in targeting the delivery, and their diagnostic applications.

Metallic nanocarriers for therapeutic peptides: Emerging solutions addressing the delivery challenges in brain ailments.

Self-assembling short peptide amphiphiles, crafted through a minimalistic approach, spontaneously generate well-ordered nanostructures, facilitating the creation of precise nanostructured biomaterials for diverse biomedical applications. The seamless integration of bioactive metal ions and nanoparticles endows them with the potential to serve as pioneering materials in combating bacterial infections. Nanomanipulation of these molecules' binary structures enables effective penetration of membranes, forming structured nanoarchitectures with antibacterial properties. Through a comprehensive exploration, we attempt to reveal the innovative potential of short peptide amphiphiles, particularly in conjugation with metal cations and nanoparticles, offering insights for future research trajectories. 

Self-assembling short peptide amphiphiles as versatile delivery agents: a new frontier in antibacterial research

Inspired by natural metallopeptides, our work focuses on engineering self-assembling nanostructures of C2-symmetric metallopeptide conjugates (MPC), Pyridine-bis-tripeptide bioprobe, uniquely detects lead (Pb2+) ions, emitting a fluorescence signal at 450 nm,... 

Metallopeptide Nanoreservoirs for Concurrent Imaging and Detoxification of Lead (Pb) from human Retinal Pigment Epithelial (hRPE1) Cells

Fluorescent gold nanoclusters (AuNCs) have shown promise as metal ion sensors. Further research into surface ligands is crucial for developing sensors that are both selective and sensitive. Here, we designed simple tripeptides to form fluorescent AuNCs, capitalizing on tyrosine’s reduction capability under alkaline conditions. We investigated tyrosine’s role in both forming AuNCs and sensing metal ions. Two tripeptides, tyrosine–cysteine–tyrosine (YCY) and serine–cysteine–tyrosine (SCY), were used to form AuNCs. YCY peptides produced AuNCs with blue and red fluorescence, while SCY peptides produced blue-emitting AuNCs. The blue fluorescence of YCY- and SCY-AuNCs was selectively quenched by Fe3+ and Cu2+, whereas red-emitting YCY-AuNC fluorescence remained stable with 13 different metal ions. The number of tyrosine residues influenced the sensor response. DLS measurements revealed different aggregation propensities in the presence of various metal ions, indicating that chelation between the peptide and target ions led to aggregation and fluorescence quenching. Highlighting the innovation of our approach, our study demonstrates the feasibility of the rational design of peptides for the formation of fluorescent AuNCs that serve as highly selective and sensitive surface ligands for metal ion sensing. This method marks an advancement over existing methods due to its dual capability in both synthesizing gold nanoclusters and detecting analytes, specifically Fe3+ and Cu2+.

Tripeptide-Assisted Gold Nanocluster Formation for Fe3+ and Cu2+ Sensing

Metallopeptide-inspired, pyridine-bis-tyrosine short peptide conjugate was developed which coordinates Hg(II) ions and hence was further used for the formation of solid mercury nanoparticles at ambient conditions. The formation of solid mercury nanoparticles was obtained from the transformation of stable mercury nanodrops which are guided by peptide nanostructures. Our results showed that initially Hg(II) ions get converted into Hg(0) nanodrops(HgNDs) and stabilized by peptide envelope which subsequently transformed into solid HgNPs with the help of time-dependent electron beam exposure under peptide nanostructure envelope. The solid HgNPs exhibit remarkable rhombohedral morphology and are found crystalline at room temperature. To the best of our knowledge, this is the first report of peptide-mediated electron beam-induced facile synthesis of solid mercury nanoparticles from less toxic Hg(II) ions at room temperature. 

Metallopeptide-inspired pyridine-bis-tyrosine peptide conjugate mediated facile room temperature synthesis of ultrafine solid mercury nanoparticles for plausible applications

The microbiota‐gut‐brain axis (GBA) plays a critical role in the development of neurodegenerative diseases. Dysbiosis of the intestinal microbiome causes a significant alteration in the gut microbiota of Alzheimer's disease (AD) patients, followed by neuroinflammatory processes. Thus, AD beginning in the gut is closely related to an imbalance in gut microbiota, and hence a multidomain approach to reduce this imbalance by exerting positive effects on the gut microbiota is needed. In one example, a tyrosine‐based short peptide amphiphile (sPA) was used to synthesize antibacterial AgNPs−sPA nanostructures. Such nanostructures showed high biocompatibility and low cytotoxicity, and therefore work as model drug delivery agents for addressing local bacterial infections. These may have therapeutic value for the treatment of microbiota‐triggered progression of neurodegenerative diseases.

Silver‐Nanoparticle‐Embedded Short Amphiphilic Peptide Nanostructures and Their Plausible Application to Reduce Bacterial Infections

Self-Responsive Biomimetic Short Lipopeptide-Based Delivery Systems for Enhanced Antibiotic Efficacy against Drug-Resistant Infections

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Metallopeptide-inspired pyridine-bis-tyrosine peptide conjugate mediated facile room temperature synthesis of ultrafine solid mercury nanoparticles for plausible applications

Silver‐Nanoparticle‐Embedded Short Amphiphilic Peptide Nanostructures and Their Plausible Application to Reduce Bacterial Infections

Self-Responsive Biomimetic Short Lipopeptide-Based Delivery Systems for Enhanced Antibiotic Efficacy against Drug-Resistant Infections