Supramolecular nanostructures assembled from synthetic peptides constitute promising scaffolds for the delivery of antigens for vaccine development. Amphiphilic peptides and self-assembling cross-β-peptides have been shown to promote cellular uptake of antigenic epitopes by antigen-presenting cells, to stimulate the innate immune system and to induce a robust antigen-specific humoral immune response. In this study, we evaluated the use of cylindrical micelles assembled from the amphiphilic β-peptide C16V3A3K3 as a vaccine nanoplatform, combining the properties of cross-β-sheet fibrils and micelles. The ectodomain of the matrix 2 protein (M2e) of the influenza A virus was conjugated with a tetra-Gly linker at the C-terminus of C16V3A3K3. The chimeric peptide assembled into biocompatible unbranched filaments that exposed the antigen on the surface, and these filaments were readily internalized by dendritic cells and activated the toll-like receptor 2/6. These cylindrical micelles induced a robust M2e-specific humoral immune response upon intramuscular immunization in mice without the need for co-administration with adjuvants. Although this strong humoral response did not translate into protection against a lethal infection with the H1N1 influenza virus, these cylindrical micelles assembled from amphiphilic β-peptides expand the repertoire of self-adjuvanted nanostructures to enhance antibody production against peptide epitopes.

We prepared three simple molecules, that we chose as representative examples of amphiphilic and bolamphiphilic amino acid derivatives: N-lauroyl-L-phenylalanine (Lau-Phe-OH), N-palmitoyl-L-phenylalanine (Pal-Phe-OH), N,N-azeloyl-L-diphenylalanine Az-(Phe-OH)2, to study the influence of the aliphatic side chain on the formation of supramolecular materials. We found that Pal-Phe-OH is a very efficient gelator in contrast with Az-(Phe-OH)2 that efficiently forms crystals, while Lau-Phe-OH forms metastable hydrogels that slowly become crystals. We demonstrated by X-ray diffraction that Lau-Phe-OH and Pal-Phe-OH easily form hetero-intermolecular hydrogen bonds between the carboxylic and amidic groups, while Az-(Phe-OH)2 forms homo-intermolecular hydrogen bonds, i. e., the typical carboxylic ring dimer and chains between the amidic functions, which leads to an extended and robust 2D hydrogen bonding network. Moreover, Lau-Phe-OH is more ordered than Pal-Phe-OH and the comparison of these results clearly indicates that the reduced order of Pal-L-Phe-OH is the main reason for the efficiency of this molecule as supergelator.

In this study, 19 tetrapeptides, each consisting of four amino acid residues, were designed and modified with oleic acid to serve as amphiphilic dispersants for anticancer drug delivery. The lipid-modified peptides (Ole-pep) were evaluated for their ability to disperse paclitaxel (Ptx), a poorly water-soluble anticancer drug. The water dispersibility of Ptx was significantly increased when peptides with two or more positively or negatively charged functional groups were used as dispersants. One specific Ole-pep demonstrated a critical micelle concentration of 0.0682 × 10-3 mol/dm3, confirming its excellent amphiphilic properties and capacity to encapsulate Ptx. Cytotoxicity studies in HeLa cells, a cell line derived from human cervical cancer cells, confirmed that the complexes with Ptx were highly cytotoxic regardless of the peptide used. Additionally, the results suggested that certain peptides, particularly those with a high number of Lys residues, exhibited cytotoxicity on their own.

The development of effective drug delivery systems is a key focus in pharmaceutical research, aiming to enhance therapeutic efficacy while minimizing adverse effects. Self-assembled nanostructures present a promising solution due to their tunable properties, biocompatibility, and ability to encapsulate and deliver therapeutic agents to specific targets. This review examines recent advancements in drug-based self-assembled nanostructures for targeted delivery applications, including drug-drug conjugates, polymeric-based architectures, biomolecules, peptides, DNA, squalene conjugates and amphiphilic drugs. Various strategies for fabricating these nanostructures are discussed, with an emphasis on the design principles and mechanisms underlying their self-assembly and potential for targeted drug delivery to specific tissues or cells. Furthermore, the integration of targeting ligands, stimuli-responsive moieties and imaging agents into these nanostructures is explored for enhanced therapeutic outcomes and real-time monitoring. Challenges such as stability, scalability and regulatory hurdles in translating these nanostructures from bench to bedside are also addressed. Drug-based self-assembled nanostructures represent a promising platform for developing next-generation targeted drug delivery systems with improved therapeutic efficacy and reduced side effects.

Nasal medications hold significant importance and are widely utilized due to their numerous advantageous properties, offering a compelling route for both local and systemic therapeutic effects. Nowadays, the development of nasal particles under 1 micrometer is in the focus of much scientific research. In our experiments, the use of innovative nanotechnology to increase the effectiveness of the active substance was of paramount importance. Our aim was to create solid nanoparticles that enable targeted and effective delivery of the active ingredient into the body. The innovation of this experimental series lies not only in highlighting the importance of amphiphilic compounds in enhancing penetration, but also in the fact that while most nasally administered formulations are in liquid form, our formulation is solid. Liquid formulations frequently suffer from the disadvantage of possible leakage during administration, which can reduce the bioavailability of the active ingredient. In our experiments we created novel drug delivery systems of finely divided powders, which, thanks to the penetration enhancers, can be successfully administered. These enhancers facilitate the swift disintegration and penetration of the particles through the membrane. This represents a new direction in nasal drug delivery methods. The results of our trials are promising in the development of innovative pharmaceutical products and outline the role of amphiphilic compounds in more efficient utilization and targeted application of active substances. According to our results it can be concluded that this innovative approach not only addresses the common issues associated with liquid nasal formulations but also paves the way for more stable and effective delivery methods. The use of finely divided powders for nasal delivery, enabled by penetration enhancers, represents a major breakthrough in the field, providing a dependable alternative to conventional liquid formulations and ensuring improved therapeutic results.

Each organelle referring to a complex multiorder architecture executes respective biological processes via its distinct spatial organization and internal microenvironment. As the assembly of biomolecules is the structural basis of living cells, creating synthetic nanoassemblies with specific physicochemical and morphological properties in living cells to interfere or couple with the natural organelle architectures has attracted great attention in precision therapeutics of cancers. In this review, we give an overview of the latest advances in the synthetic nanoassemblies for precise organelle regulation, including the formation mechanisms, triggering strategies, and biomedical applications in precision therapeutics. We summarize the emerging material systems, including polymers, peptides, and deoxyribonucleic acids (DNAs), and their respective intermolecular interactions for intercellular synthetic nanoassemblies, and highlight their design principles in constructing precursors that assemble into synthetic nanoassemblies targeting specific organelles in the complex cellular environment. We further showcase the developed intracellular synthetic nanoassemblies targeting specific organelles including mitochondria, the endoplasmic reticulum, lysosome, Golgi apparatus, and nucleus and describe their underlying mechanisms for organelle regulation and precision therapeutics for cancer. Last, the essential challenges in this field and prospects for future precision therapeutics of synthetic nanoassemblies are discussed. This review should facilitate the rational design of organelle-targeting synthetic nanoassemblies and the comprehensive recognition of organelles by materials and contribute to the deep understanding and application of the synthetic nanoassemblies for precision therapeutics.

Promoting angiogenesis and modulating the inflammatory microenvironment are promising strategies for treating acute myocardial infarction (MI). Macrophages are crucial in regulating inflammation and influencing angiogenesis through interactions with endothelial cells. However, current therapies lack a comprehensive assessment of pathological and physiological subtleties, resulting in limited myocardial recovery. In this study, legumain-guided ferulate-peptide nanofibers (LFPN) are developed to facilitate the interaction between macrophages and endothelial cells in the MI lesion and modulate their functions. LFPN exhibits enhanced ferulic acid (FA) aggregation and release, promoting angiogenesis and alleviating inflammation. The multifunctional role of LFPN is validated in cells and an MI mouse model, where it modulated macrophage polarization, attenuated inflammatory responses, and induces endothelial cell neovascularization compare to FA alone. LFPN supports the preservation of border zone cardiomyocytes by regulating inflammatory infiltration in the ischemic core, leading to significant functional recovery of the left ventricle. These findings suggest that synergistic therapy exploiting multicellular interaction and enzyme guidance may enhance the clinical translation potential of smart-responsive drug delivery systems to treat MI. This work emphasizes macrophage-endothelial cell partnerships as a novel paradigm to enhance cell interactions, control inflammation, and promote therapeutic angiogenesis.

Cancer is a serious threat to human health because of its high annual mortality rate. It has attracted significant attention in healthcare, and identifying effective strategies for the treatment and relief of cancer pain requires urgency. Drug delivery systems (DDSs) offer the advantages of excellent efficacy, low cost, and low toxicity for targeting drugs to tumor sites. In recent decades, copolymer carriers based on poly(phenylalanine) (PPhe) and poly(3,4-dihydroxy-L-phenylalanine) (PDopa) have been extensively investigated owing to their good biocompatibility, biodegradability, and controllable stimulus responsiveness, which have resulted in DDSs with loading and targeted delivery capabilities. In this review, we introduce the synthesis of PPhe and PDopa, highlighting the latest proposed synthetic routes and comparing the differences in drug delivery between PPhe and PDopa. Subsequently, we summarize the various applications of PPhe and PDopa in nanoscale-targeted DDSs, providing a comprehensive analysis of the drug release behavior based on different stimulus-responsive carriers using these two materials. In the end, we discuss the challenges and prospects of polypeptide-based DDSs in the field of cancer therapy, aiming to promote their further development to meet the growing demands for treatment.

The development of peptide-based materials is one of the most challenging aspects of biomaterials research in recent years. The assembly of peptides is mainly controlled by forces such as hydrogen bonding, hydrophobic interaction, electrostatic interaction, and π-π accumulation. Peptides have unique advantages such as simple structure, easy synthesis, good biocompatibility, non-toxicity, easy modification, etc. These factors make peptides turn into ideal biomedical materials, and they have a broad application prospect in biomedical materials, and thus have received wide attention. In this review, the mechanism and classification of peptide self-assembly and its applications in biomedicine and hydrogels were introduced.

Calcium supplementation has been shown to be efficacious in mitigating the progression of senile osteoporosis (SOP) and reducing the incidence of osteoporotic fractures resulting from prolonged calcium shortage. In this study, Grifola frondosa (GF) peptides-calcium chelate were synthesized through the interaction between peptide from GF and CaCl2. The chelation reaction was shown to involve the participation of the amino and carboxyl groups in the peptide, as revealed by scanning electron microscope, Fourier-transform infrared, and ultraviolet spectrophotometry. Furthermore, a mouse model of (SOP) induced by d-galactose was established (SCXK-2018-0004). Results demonstrated that low dosage of low-molecular weight GF peptides-calcium chelates (LLgps-Ca) could significantly improve serum index and pathological features of bone tissue and reduce bone injury. Further research suggested that LLgps-Ca could ameliorate SOP by modulating the disrupted metabolic pathway, which includes focal adhesion, extracellular matrix receptor interaction, and PI3K-Akt signaling pathway. Using Western blot, the differentially expressed proteins were further confirmed. Thus, calciumchelating peptides from GF could serve as functional calcium agents to alleviate SOP.

Self-assembled peptide-based nanobiomaterials exhibit promising prospects for drug delivery applications owing to their commendable biocompatibility and biodegradability, facile tissue uptake and utilization, and minimal or negligible unexpected toxicity. TFF3 is an active peptide autonomously secreted by gastric mucosal cells, possessing multiple biological functions. It acts on the surface of the gastric mucosa, facilitating the repair process of gastric mucosal damage. However, when used as a drug, TFF3 faces significant challenges, including short retention time in the gastric mucosal cavity and deactivation due to degradation by stomach acid. In response to this challenge, we developed a self-assembled short peptide hydrogel, Rqdl10, designed as a delivery vehicle for TFF3. Our investigation encompasses an assessment of its properties, biocompatibility, controlled release of TFF3, and the mechanism underlying the promotion of gastric mucosal injury repair. Congo red/aniline blue staining revealed that Rqdl10 promptly self-assembled in PBS, forming hydrogels. Circular dichroism spectra indicated the presence of a stable β-sheet secondary structure in the Rqdl10 hydrogel. Cryo-scanning electron microscopy and atomic force microscopy observations demonstrated that the Rqdl10 formed vesicle-like structures in the PBS, which were interconnected to construct a three-dimensional nanostructure. Moreover, the Rqdl10 hydrogel exhibited outstanding biocompatibility and could sustainably and slowly release TFF3. The utilization of the Rqdl10 hydrogel as a carrier for TFF3 substantially augmented its proliferative and migratory capabilities, while concurrently bolstering its anti-inflammatory and anti-apoptotic attributes following gastric mucosal injury. Our findings underscore the immense potential of the self-assembled peptide hydrogel Rqdl10 for biomedical applications, promising significant contributions to healthcare science.

Retroviral gene delivery is the key technique for in vitro and ex vivo gene therapy. However, inefficient virion-cell attachment resulting in low gene transduction efficacy remains a major challenge in clinical applications. Adjuvants for ex vivo therapy settings need to increase transduction efficiency while being easily removed or degraded post-transduction to prevent the risk of venous embolism after infusing the transduced cells back to the bloodstream of patients, yet no such peptide system have been reported thus far. In this study, peptide amphiphiles (PAs) with a hydrophobic fatty acid and a hydrophilic peptide moiety that reveal enhanced viral transduction efficiency are introduced. The PAs form β-sheet-rich fibrils that assemble into positively charged aggregates, promoting virus adhesion to the cell membrane. The block-type amphiphilic sequence arrangement in the PAs ensures efficient cell-virus interaction and biodegradability. Good biodegradability is observed for fibrils forming small aggregates and it is shown that via molecular dynamics simulations, the fibril-fibril interactions of PAs are governed by fibril surface hydrophobicity. These findings establish PAs as additives in retroviral gene transfer, rivalling commercially available transduction enhancers in efficiency and degradability with promising translational options in clinical gene therapy applications.

Neurological disorders pose a significant burden on individuals and society, affecting millions worldwide. These disorders, including but not limited to Alzheimer's disease, Parkinson's disease, and Huntington's disease, often have limited treatment options and can lead to progressive degeneration and disability. Gene editing technologies, including Zinc Finger Nucleases (ZFN), Transcription Activator-Like Effector Nucleases (TALEN), and Clustered Regularly Interspaced Short Palindromic Repeats-associated Protein 9 (CRISPR-Cas9), offer a promising avenue for potential cures by targeting and correcting the underlying genetic mutations responsible for neurologic disorders. However, efficient delivery methods are crucial for the successful application of gene editing technologies in the context of neurological disorders. The central nervous system presents unique challenges to treatment development due to the blood-brain barrier, which restricts the entry of large molecules. While viral vectors are traditionally used for gene delivery, nonviral delivery methods, such as nanoparticle-mediated delivery, offer safer alternatives that can efficiently transport gene editing components. Herein we aim to introduce the three main gene editing nucleases as nonviral treatments for neurologic disorders, the delivery barriers associated with brain targeting, and the current nonviral techniques used for brain-specific delivery. We highlight the challenges and opportunities for future research in this exciting and growing field that could lead to blood-brain barrier bypassing therapeutic gene editing.

The health benefits of anthocyanins have attracted extensive research interest. However, anthocyanins are sensitive to certain environmental and gastrointestinal conditions and have low oral bioavailability. It has been reported that delivery systems made in different ways could improve the stability, bioavailability and bioactivity of anthocyanins. This present review summarizes the factors affecting the stability of anthocyanins and the reasons for poor bioavailability, and various technologies for encapsulation of anthocyanins including microcapsules, nanoemulsions, microemulsions, Pickering emulsions, nanoliposomes, nanoparticles, hydrogels and co-assembly with amphiphilic peptides were discussed. In particular, the effects of these encapsulation technologies on the stability, bioavailability and bioactivities of anthocyanins in vitro and in vivo experiments are reviewed in detail, which provided scientific insights for anthocyanins encapsulation methods. However, the application of anthocyanins in food industry as well as the biological fate and functional pathways in vivo still need to be further explored.

"Green" strategies to build up novel organic nanocarriers with bioperformance are modern trends in nanotechnology. In this way, the valorization of bio-wastes and the use of living systems to develop multifunctional organic and biogenic nanocarriers (OBNs) have revolutionized the nanotechnological and biomedical fields. This paper is a comprehensive review related to OBNs for bioactives' delivery, providing an overview of the reports on the past two decades. In the first part, several classes of bioactive compounds and their therapeutic role are briefly presented. A broad section is dedicated to the main categories of organic and biogenic nanocarriers. The major challenges regarding the eco-design and the fate of OBNs are suggested to overcome some toxicity-related drawbacks. Future directions and opportunities, and finding "green" solutions for solving the problems related to nanocarriers, are outlined in the final of this paper. We believe that through this review, we will capture the attention of the readers and will open new perspectives for new solutions/ideas for the discovery of more efficient and "green" ways in developing novel bioperformant nanocarriers for transporting bioactive agents.

Cyclophilin D (CypD) is a mitochondrial matrix peptidyl prolidase that regulates the mitochondrial permeability transition pore. Inhibition of CypD was suggested as a therapeutic strategy for acute pancreatitis. Peptide inhibitors emerged as novel binding ligand for blocking receptor activity. In this study, we present our computational approach for designing peptide inhibitors of CypD. The 3-D structure of random peptides were built, and docked into the active center of CypD using Rosetta script integrated FlexPepDock module. The peptide displayed the lowest binding energy against CypD was further selected for virtual iterative mutation based on virtual mutagenesis and molecular docking. Finally, the top 5 peptides with the lowest binding energy was selected for validating their affinity against CypD using inhibitory assay. We showed 4 out of the selected 5 peptides were capable for blocking the activity of CypD, while WACLQ display the strongest affinity against CypD, which reached 0.28 mM. The binding mechanism between WACLQ and CypD was characterized using molecular dynamics simulation. Here, we proved our approach can be a robust method for screening peptide inhibitors.

De novo designed peptides that self-assemble into cross-β rich fibrillar biomaterials have been pursued as an innovative platform for the development of adjuvant- and inflammation-free vaccines. However, they share structural and morphological properties similar to amyloid species implicated in neurodegenerative diseases, which has been a long-standing concern for their successful translation. Here, we comprehensively characterize the amyloidogenic character of the amphipathic self-assembling cross-β peptide KFE8, compared to pathological amyloid and amyloid-like proteins α-synuclein (α-syn) and TDP-43. Further, we developed plasmid-based DNA vaccines with the KFE8 backbone serving as a scaffold for delivery of a GFP model antigen. We find that expression of tandem repeats of KFE8 is non-toxic and efficiently cleared by autophagy. We also demonstrate that preformed KFE8 fibrils do not cross-seed amyloid formation of α-syn in mammalian cells compared to α-syn preformed fibrils. In mice, vaccination with plasmids encoding the KFE32-GFP fusion protein elicited robust immune responses, inducing production of significantly higher levels of anti-GFP antibodies compared to soluble GFP. Antigen-specific CD8+T cells were also detected in the spleens of vaccinated mice and cytokine profiles from antigen recall assays indicate a balanced Th1/Th2 response. These findings illustrate that cross-β-rich peptide nanofibers have distinct physicochemical properties from those of pathological amyloidogenic proteins, and are an attractive platform for the development of DNA vaccines with self-adjuvanting properties and improved safety profiles. STATEMENT OF SIGNIFICANCE: Biomaterials comprised of self-assembling peptides hold great promise for the development of new vaccines that do not require use of adjuvants. However, these materials have safety concerns, as they self-assemble into cross-β rich fibrils that are structurally similar to amyloid species implicated in disease. Here, we comprehensively study the properties of these biomaterials. We demonstrate that they have distinct properties from pathological proteins. They are non-toxic and do not trigger amyloidogenesis. Vaccination of these materials in mice elicited a robust immune response. Most excitingly, our work suggests that this platform could be used to develop DNA-based vaccines, which have few storage requirements. Further, due to their genetic encoding, longer sequences can be generated and the vaccines will be amenable to modification.

Surfactant like peptides (SLPs) are a class of amphiphilic peptides widely used for drug delivery and tissue engineering. However, there are very few reports on their application for gene delivery. The current study was aimed at development of two new SLPs, named (IA)4K and (IG)4K, for selective delivery of antisense oligodeoxynucleotides (ODNs) and small interfering RNA (siRNA) to cancer cells. The peptides were synthesized by Fmoc solid phase synthesis. Their complexation with nucleic acids was studied by gel electrophoresis and DLS. The transfection efficiency of the peptides was assessed in HCT 116 colorectal cancer cells and human dermal fibroblasts (HDFs) using high content microscopy. The cytotoxicity of the peptides was assessed by standard MTT test. The interaction of the peptides with model membranes was studied using CD spectroscopy. Both SLPs delivered siRNA and ODNs to HCT 116 colorectal cancer cells with high transfection efficiency which was comparable to the commercial lipid-based transfection reagents, but with higher selectivity for HCT 116 compared to HDFs. Moreover, both peptides exhibited very low cytotoxicity even at high concentrations and long exposure time. The current study provides more insights into the structural features of SLPs required for nucleic acid complexation and delivery and can therefore serve as a guide for the rational design of new SLPs for selective gene delivery to cancer cells to minimize the adverse effects in healthy tissues.

Self-assembly is a growth mechanism in nature to apply local interactions forming a minimum energy structure. Currently, self-assembled materials are considered for biomedical applications due to their pleasant features, including scalability, versatility, simplicity, and inexpensiveness. Self-assembled peptides can be applied to design and fabricate different structures, such as micelles, hydrogels, and vesicles, by diverse physical interactions between specific building blocks. Among them, bioactivity, biocompatibility, and biodegradability of peptide hydrogels have introduced them as versatile platforms in biomedical applications, such as drug delivery, tissue engineering, biosensing, and treating different diseases. Moreover, peptides are capable of mimicking the microenvironment of natural tissues and responding to internal and external stimuli for triggered drug release. In the current review, the unique characteristics of peptide hydrogels and recent advances in their design, fabrication, as well as chemical, physical, and biological properties are presented. Additionally, recent developments of these biomaterials are discussed with a particular focus on their biomedical applications in targeted drug delivery and gene delivery, stem cell therapy, cancer therapy and immune regulation, bioimaging, and regenerative medicine.

Four peptide amphiphiles (PA1-4) with different degrees of polymerization (DP = 40, 15, 10, and 6) were synthesized by Fuchs-Farthing and ring-opening polymerization followed by post-polymerization modification, as fully characterized by ¹H NMR, FT-IR, gel permeation chromatography, and circular dichroism (CD) spectroscopy. It was found that PAs could self-assemble to form regular spherical micelles in low-concentration (about 1 mg/mL) aqueous solution, which had different contents of secondary structures and mainly adopted random coil conformations. The water solubility of PAs increases with the increase of DP, the polypeptide chain stretches randomly in water, the β-sheets decrease, and the random coil conformations dominate. When the pH of PA solution decreases or increases, intramolecular hydrogen bonds break, and molecular chains stretch, leading to a decrease of α-helix, turn conformations, and an increase of β-sheets. Meanwhile, the particle size of micelles increases. At around 0.4 mg/mL, the hemolysis ability of PA2 is negligible at pH 7.4 and 6.5 and about 33% at pH 5.5. Cisplatin (CDDP) was linked to micelles by coordination bonds to explore their potential as drug carriers, exhibiting controlled pH and reduction in dual drug release effects. MTT assay showed that the HeLa cell viability was 78% when cultured in the 13.5 μg/mL PA2 blank micelles for 2 days, while the cell viability was 60% in the CDDP-loaded micelles. Furthermore, a high concentration of PA2 (about 100 mg/mL) could self-assemble into a fibrous hydrogel at pH 5.5, which self-healed 2 h after incision and self-degraded 71% within 14 days. The CDDP-loaded fiber hydrogel exhibited a sustained release effect similar to the CDDP-loaded micelles. The cytotoxicity of CDDP-loaded fibers at 48 h was detected to be the same as that of the same amount of CDDP, and the cell viability was 7%. Therefore, we provide a new strategy for the synthesis of amphiphilic peptides with potential applications in nano-drug carriers and cancer therapy.

In recent years, self-assembled peptide nanotechnology has attracted a great deal of attention for its ability to form various regular and ordered structures with diverse and practical functions. Self-assembled peptides can exist in different environments and are a kind of medical bio-regenerative material with unique structures. These materials have good biocompatibility and controllability and can form nanoparticles, nanofibers and hydrogels to perform specific morphological functions, which are widely used in biomedical and material science fields. In this paper, the properties of self-assembled peptides, their influencing factors and the nanostructures that they form are reviewed, and the applications of self-assembled peptides as drug carriers are highlighted. Finally, the prospects and challenges for developing self-assembled peptide nanomaterials are briefly discussed.

Cervical cancer is the 4th most common type of cancer in women world-wide. Many factors play a role in cervical cancer development/progression that include genetics, social behaviors, social determinants of health, and even the microbiome. The prevalence of HPV infections and cervical cancer is high and often understudied among Native American communities. While effective HPV vaccines exist, less than 60% of 13- to 17-year-olds in the general population are up to date on their HPV vaccination as of 2020. Vaccination rates are higher among Native American adolescents, approximately 85% for females and 60% for males in the same age group. Unfortunately, the burden of cervical cancer remains high in many Native American populations. In this paper, we will discuss HPV infection, vaccination and the cervicovaginal microbiome with a Native American perspective. We will also provide insight into new strategies for developing novel methods and therapeutics to prevent HPV infections and limit HPV persistence and progression to cervical cancer in all populations.