Development Of Nanomedicines Research Articles

Integrated Computational and Experimental Framework for Inverse Screening of Candidate Antibacterial Nanomedicine.

Nanomedicine is promising for disease prevention and treatment, but there are still many challenges that hinder its rapid development. A major challenge is to efficiently seek candidates with the desired therapeutic functions from tremendously available materials. Here, we report an integrated computational and experimental framework to seek alloy nanoparticles from the Materials Project library for antibacterial applications, aiming to learn the inverse screening concept from traditional medicine for nanomedicine. Because strong peroxidase-like catalytic activity and weak toxicity to normal cells are the desired material properties for antibacterial usage, computational screening implementing theoretical prediction models of catalytic activity and cytotoxicity is first conducted to select the candidates. Then, experimental screening based on scanning probe block copolymer lithography is used to verify and refine the computational screening results. Finally, the best candidate AuCu3 is synthesized in solution and its antibacterial performance over other nanoparticles against S. aureus and E. coli. is experimentally confirmed. The results show the power of inverse screening in accelerating the research and development of antibacterial nanomedicine, which may inspire similar strategies for other nanomedicines in the future.

Dual drug-loaded metal-phenolic networks for targeted magnetic resonance imaging and synergistic chemo-chemodynamic therapy of breast cancer.

The development of nanomedicines with simplified compositions and synergistic theranostic functionalities remains a great challenge. Herein, we develop a simple method to integrate both atovaquone (ATO, a mitochondrial inhibitor) and cisplatin within tannic acid (TA)-iron (Fe) networks coated with hyaluronic acid (HA) for targeted magnetic resonance (MR) imaging-guided chemo-chemodynamic synergistic therapy. The formed TFP@ATO-HA displayed good colloidal stability with a mean size of 95.5 nm, which could accumulate at tumor sites after circulation and be specifically taken up by metastatic 4T1 cells overexpressing CD44 receptors. In the tumor microenvironment, TFP@ATO-HA could release ATO/cisplatin and Fe3+ in a pH-responsive manner, deplete glutathione, and generate reactive oxygen species with endogenous H2O2 for chemodynamic therapy (CDT). Additionally, ATO could enhance chemotherapeutic efficacy by inhibiting mitochondrial respiration, relieving hypoxia, and amplifying the CDT effect by decreasing intracellular pH and elevating Fenton reaction efficiency. In vivo experiments demonstrated that TFP@ATO-HA could effectively inhibit tumor growth and suppress lung metastases without obvious systemic toxicity. Furthermore, TFP@ATO-HA exhibited a r1 relaxivity of 2.6 mM-1 s-1 and targeted MR imaging of 4T1 tumors. Dual drug-loaded metal-phenolic networks can be easily prepared and act as effective theranostic nanoplatforms for targeted MR imaging and synergistic chemo-chemodynamic therapy.

Reviewing Advances in Rheumatoid Arthritis Treatment: From Disease-modifying Antirheumatic Drugs to Innovative Drug Delivery Systems

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by inflammatory processes that result in joint swelling, inflammation, and the onset of pain. This discomfort and pathological condition exhibit a gradual rise in scale and become more intense. Even though pharmacotherapy like disease-modifying antirheumatic drugs (DMARDs) and biologics has improved, there is still a need for more focused treatments that cause less harm. This study examines how treatments for RA have changed over time, focusing on the shift from traditional medicines to new, creative ways to combine medicine with immune-engineering therapies. DMARDs are still the most common way to treat RA. On the other hand, biologics and Janus kinase inhibitors are options for people who do not react to their first medications. The development of nanomedicines and hydrogels is an exciting new area of study because they make it possible for more precise spread and less overall toxicity of the medicine. The early research suggests that these innovative approaches could greatly improve the effectiveness of therapy by delivering drugs directly to the site of inflammation while also reducing the severity of any side effects that might occur. RA care is quickly expanding beyond the traditional use of drugs to include more modern ways of managing medications and also personalized healing methods.

Biopolymeric nanocarriers in cancer therapy: unleashing the potency of bioactive anticancer compounds for enhancing drug delivery.

Effective cancer treatment is becoming a global concern, and recent developments in nanomedicine are essential for its treatment. Cancer is a severe metabolic syndrome that affects the human population and is a significant contributing factor to deaths globally. In science, nanotechnology offers rapidly developing delivery methods for natural bioactive compounds that are becoming increasingly prominent and can be used to treat diseases in a site-specific way. Chemotherapy and radiotherapy are conventional approaches for preventing cancer progression and have adverse effects on the human body. Many chemically synthesized drugs are used as anticancer agents, but they have several side effects; hence, they are less preferred. Medicinal plants and marine microorganisms represent a vast, mostly untapped reservoir of bioactive compounds for cancer treatment. However, they have several limitations, including nonspecific targeting, weak water solubility and limited therapeutic potential. An alternative option is the use of biopolymeric nanocarriers, which can generate effective targeted treatment therapies when conjugated with natural anticancer compounds. The present review focuses on biopolymeric nanocarriers utilizing natural sources as anticancer drugs with improved tumor-targeting efficiency. This review also covers various natural anticancer compounds, the advantages and disadvantages of natural and synthetic anticancer compounds, the problems associated with natural anticancer drugs and the advantages of biopolymeric nanocarriers over synthetic nanocarriers as drug delivery agents. This review also discusses various biopolymeric nanocarriers for enhancing the controlled delivery of anticancer compounds and the future development of nanomedicines for treating cancer.

Deep learning for automatic organ and tumor segmentation in nanomedicine pharmacokinetics.

Rationale: Multimodal imaging provides important pharmacokinetic and dosimetry information during nanomedicine development and optimization. However, accurate quantitation is time-consuming, resource intensive, and requires anatomical expertise. Methods: We present NanoMASK: a 3D U-Net adapted deep learning tool capable of rapid, automatic organ segmentation of multimodal imaging data that can output key clinical dosimetry metrics without manual intervention. This model was trained on 355 manually-contoured PET/CT data volumes of mice injected with a variety of nanomaterials and imaged over 48 hours. Results: NanoMASK produced 3-dimensional contours of the heart, lungs, liver, spleen, kidneys, and tumor with high volumetric accuracy (pan-organ average %DSC of 92.5). Pharmacokinetic metrics including %ID/cc, %ID, and SUVmax achieved correlation coefficients exceeding R = 0.987 and relative mean errors below 0.2%. NanoMASK was applied to novel datasets of lipid nanoparticles and antibody-drug conjugates with a minimal drop in accuracy, illustrating its generalizability to different classes of nanomedicines. Furthermore, 20 additional auto-segmentation models were developed using training data subsets based on image modality, experimental imaging timepoint, and tumor status. These were used to explore the fundamental biases and dependencies of auto-segmentation models built on a 3D U-Net architecture, revealing significant differential impacts on organ segmentation accuracy. Conclusions: NanoMASK is an easy-to-use, adaptable tool for improving accuracy and throughput in imaging-based pharmacokinetic studies of nanomedicine. It has been made publicly available to all readers for automatic segmentation and pharmacokinetic analysis across a diverse array of nanoparticles, expediting agent development.

A gold nanocluster/MIL-100(Fe) bimodal nanovector for the therapy of inflammatory disease through attenuation of Toll-like receptor signaling.

A better understanding of the molecular and cellular events involved in the inflammation process has opened novel perspectives in the treatment of inflammatory diseases, particularly through the development of well-designed nanomedicines. Here we describe the design of a novel class of anti-inflammatory nanomedicine (denoted as Au@MIL) synthesized through a one-pot, cost-effective and green approach by coupling a benchmark mesoporous iron(III) carboxylate metal organic framework (MOF) (i.e. MIL-100(Fe)) and glutathionate protected gold nanoclusters (i.e. Au25SG18 NCs). This nano-carrier exhibits low toxicity and excellent colloidal stability combined with the high loading capacity of the glucocorticoid dexamethasone phosphate (DexP) whose pH-dependent delivery was observed. The drug loaded Au@MIL nanocarrier shows high anti-inflammatory activity due to its capacity to specifically hinder inflammatory cell growth, scavenge intracellular reactive oxygen species (ROS) and downregulate pro-inflammatory cytokine secretion. In addition, this formulation has the capacity to inhibit the Toll-like receptor (TLR) signaling cascade namely the nuclear factor kappa B (NF-κB) and the interferon regulatory factor (IRF) pathways. This not only provides a new avenue for the nanotherapy of inflammatory diseases but also enhances our fundamental knowledge of the role of nanoMOF based nanomedicine in the regulation of innate immune signaling.

Microbe-material hybrids for therapeutic applications.

As natural living substances, microorganisms have emerged as useful resources in medicine for creating microbe-material hybrids ranging from nano to macro dimensions. The engineering of microbe-involved nanomedicine capitalizes on the distinctive physiological attributes of microbes, particularly their intrinsic "living" properties such as hypoxia tendency and oxygen production capabilities. Exploiting these remarkable characteristics in combination with other functional materials or molecules enables synergistic enhancements that hold tremendous promise for improved drug delivery, site-specific therapy, and enhanced monitoring of treatment outcomes, presenting substantial opportunities for amplifying the efficacy of disease treatments. This comprehensive review outlines the microorganisms and microbial derivatives used in biomedicine and their specific advantages for therapeutic application. In addition, we delineate the fundamental strategies and mechanisms employed for constructing microbe-material hybrids. The diverse biomedical applications of the constructed microbe-material hybrids, encompassing bioimaging, anti-tumor, anti-bacteria, anti-inflammation and other diseases therapy are exhaustively illustrated. We also discuss the current challenges and prospects associated with the clinical translation of microbe-material hybrid platforms. Therefore, the unique versatility and potential exhibited by microbe-material hybrids position them as promising candidates for the development of next-generation nanomedicine and biomaterials with unique theranostic properties and functionalities.

Fluorescent Techniques for RNA Detection in Nanoparticles.

The utilization of drug delivery systems, such as lipid nanoparticles and polyplexes/micelleplexes, has shown promise in intracellularly delivering nucleic acids for addressing various diseases. Accurate quantification of the nucleic acid cargo within nanoparticles is essential for the development of safe and effective nanomedicines. Currently, the RiboGreen and SYBR Gold methods are regarded as standard techniques for the precise quantification of RNA in lipid nanoparticles and polyplexes/micelleplexes, respectively. In this chapter, we present a comprehensive protocol for the precise evaluation of the encapsulation efficiency in such formulations using these methods. Additionally, we offer detailed instructions for nanoparticle preparation, characterization, and a comparative analysis of the sensitivity of both methods in quantifying unencapsulated siRNA.

Brain Targeting Nanomedicines: Pitfalls and Promise.

Brain diseases are the most devastating problem among the world's increasingly aging population, and the number of patients with neurological diseases is expected to increase in the future. Although methods for delivering drugs to the brain have advanced significantly, none of these approaches provide satisfactory results for the treatment of brain diseases. This remains a challenge due to the unique anatomy and physiology of the brain, including tight regulation and limited access of substances across the blood-brain barrier. Nanoparticles are considered an ideal drug delivery system to hard-to-reach organs such as the brain. The development of new drugs and new nanomaterial-based brain treatments has opened various opportunities for scientists to develop brain-specific delivery systems that could improve treatment outcomes for patients with brain disorders such as Alzheimer's disease, Parkinson's disease, stroke and brain tumors. In this review, we discuss noteworthy literature that examines recent developments in brain-targeted nanomedicines used in the treatment of neurological diseases.

Metabolomics-derived biomarkers for biosafety assessment of Gd-based nanoparticle magnetic resonance imaging contrast agents.

With the rapid development of nanotechnology and biomedicine, numerous gadolinium (Gd)-based nanoparticle MRI contrast agents have been widely investigated. Due to the unique physicochemical properties of nanoparticles and the complexity of biological systems, the biosafety of Gd-based nanoparticle MRI contrast agents has been paid more and more attention. Herein, for the first time, we employed an ultra-high performance liquid chromatography-electrospray ionization quadrupole time-of-flight/mass spectrometry (UPLC-ESI-QTOF/MS)-based metabolomics approach to investigate the potential toxicity of Gd-based nanoparticle MRI contrast agents. In this work, NaGdF4 and PEG-NaGdF4 nanoparticles were successfully constructed and selected as the representative Gd-based nanoparticle MRI contrast agents for the metabolomics analysis. Based on the results of metabolomics, more metabolic biomarkers and pathways were identified in the NaGdF4 group than those in the PEG-NaGdF4 group. Careful analysis of these metabolic biomarkers and pathways suggested that NaGdF4 nanoparticles induced disturbance of pyrimidine and purine metabolism, inflammatory response, and kidney injury to a certain extent compared with PEG-NaGdF4 nanoparticles. These results indicated that Gd-based nanoparticle contrast agents modified with PEG had better biosafety. Additionally, it was demonstrated that the discovery of characteristic metabolomics biomarkers induced by nanoparticles would provide a new approach for biosafety assessment and stimulate the development of nanomedicine.

Electronic band structure modulation for sonodynamic therapy.

Sonodynamic therapy (SDT) is a burgeoning and newfangled therapy modality with great application potential. Sonosensitizers are essential factors used to ensure the effectiveness of SDT. For the past few years, a lot of scientists have discovered many valid ways to refine and improve the performance of SDT. Among these methods, modulating the electronic band structure of sonosensitizers is one of the eminent measures to improve SDT, but relevant research studies on this are still unsatisfactory for actual transformation. Herein, this review provides a brief and comprehensive introduction of common ways to modulate electronic band structure, such as forming defects, doping, piezoelectric effect and heterostructure. Then, some nanomaterials with excellent properties that can be used as a sonosensitizer to enhance the SDT effect by modulating electronic band structure are overviewed, such as Ti-based, Zn-based, Bi-based, noble metal-based and MOF-based nanomaterials. At the same time, this paper also discusses the problems and challenges that may be encountered in the future application progress of SDT. In conclusion, the strategy of enhancing SDT through modulating electronic band structure will promote the rapid development of nanomedicine and provide a great research direction for SDT.

Magnetic Double Hydrogen Artesunate Nano Liposome on CAL Tongue Squamous Carcinoma and Laryngeal Hep-2-27 Cell Lines: An In Vitro Study

With the continuous development of nanomedicine, scholars have reported many studies on the application of nanocarriers to improve the efficiency of tumor diagnosis and treatment. We designed magnetic nanoparticles combined with liposomes to carry DHA (DHA-MAG-NL) nanoparticles to improve the biocompatibility of DHA, protect DHA activity, and increase DHA blood concentration. To study the inhibitory effect of magnetic dihydroartemisinin nano-liposomes on the proliferation of human tongue squamous cell carcinoma CAL-27 cell line and laryngeal carcinoma Hep-2 cell line In Vitro. The effect of DHA-Mag-NL concentration gradient on the proliferation of Hep-2 and Cal-27 cells at different intervention times was detected by MTT assay. The effects of DHA concentration of 40 μM on the cell cycle and apoptosis of Hep-2 and Cal-27 were analyzed by flow cytometry. Statistical analysis showed that DHA-Mag-NL had a weak inhibitory effect on Cal-27 cells. The apoptosis-promoting effect of DHA-Mag-NL on Cal-27 tumor cells was weaker than that of DHA for 24 h. We concluded that DHA-Mag-NL can inhibit the proliferation of Hep-2 and Cal-27 tumor cells and promote apoptosis, which is dependent on drug dose and intervention time.

Metastable FeSe2 nanosheets as a one-for-all platform for stepwise synergistic tumor therapy.

The urgent need to curb the rampant rise in cancer has impelled the rapid development of nanomedicine. Under the above issue, transition metal compounds have received special attention considering their physicochemical and biochemical properties. However, how to take full advantage of the valuable characteristics of nanomaterials based on their spatial structures and chemical components for synergistic tumor therapy is a worthwhile exploration. In this work, a tailored two-dimensional (2D) FeSe2 nanosheet (NS) platform is proposed, which integrates enzyme activity and drug efficacy through the regulation of itsstability. Specifically, metastable FeSe2 NSs can serve as dual nanozymes in an intact state, depleting GSH and increasing ROS to induce oxidative stress in the tumor microenvironment (TME). With the gradual degradation of the FeSe2 in TME, its degraded products can amplify the Fenton reaction and GSH consumption, enhance the expression of inflammatory factors, and achieve effective near-infrared (NIR)-light irradiation-enhanced synergistic photothermal therapy (PTT) and chemodynamic therapy (CDT). Our exploration further confirmed such a strategy that may integrate carrier activity and drug action into a metastable nanoplatform for tumor synergistic therapy. These results prompt the consideration of the rational design of a one-for-all carrier that can exhibit multifunctional properties and nanomedicine efficacy for versatile therapeutic applications in the future.

In situ characterization techniques of protein corona around nanomaterials.

Nanoparticles (NPs) inevitably interact with proteins upon exposure to biological fluids, leading to the formation of an adsorption layer known as the "protein corona". This corona imparts NPs with a new biological identity, directly influencing their interactions with living systems and dictating their fates in vivo. Thus, gaining a comprehensive understanding of the dynamic interplay between NPs and proteins in biological fluids is crucial for predicting therapeutic effects and advancing the clinical translation of nanomedicines. Numerous methods have been established to decode the protein corona fingerprints. However, these methods primarily rely on prior isolation of NP-protein complex from the surrounding medium by centrifugation, resulting in the loss of outer-layer proteins that directly interact with the biological system and determine the in vivo fate of NPs. We discuss here separation techniques as well as in situ characterization methods tailored for comprehensively unraveling the inherent complexities of NP-protein interactions, highlighting the challenges of in situ protein corona characterization and its significance for nanomedicine development and clinical translation.

Bibliometric and visualized analysis of cancer nanomedicine from 2013 to 2023.

Cancer nanomedicine has been an emerging field for drug development against malignant tumors during the past three decades. A bibliometric analysis was performed to characterize the current international trends and present visual representations of the evolution and emerging trends in the research and development of nanocarriers for cancer treatment. This study employed bibliometric analysis and visualization techniques to analyze the literature on antitumor nanocarriers published between 2013 and 2023. A total of 98,980 articles on antitumor nanocarriers were retrieved from the Web of Science Core Collection (WoSCC) database and analyzed using the Citespace software for specific characteristics such as publication year, countries/regions, organizations, keywords, and references. Network visualization was constructed by VOSviewer and Citespace. From 2013 to 2023, the annual global publications increased 7.39 times, from 1851 to 13,683. People's Republic of China (2588 publications) was the most productive country. Chinese Academy of Sciences (298 publications) was the most productive organization. The top 5 high-frequency keywords were "nanoparticles," "drug delivery," "nanomedicine," "cancer," and "nanocarriers." The keywords with the strongest citation bursts recently were "cancer immunotherapy," "microenvironment," "antitumor immunity," etc., which indicated the emerging frontiers of antitumor nanomedicine. The co-occurrence cluster analysis of the keywords formed 6 clusters, and most of the top 10 publications by citation counts focused on cluster #1 (nanocarriers) and cluster #2 (cancer immunotherapy). We further provided insightful discussions into the identified subtopics to help researchers gain more details of current trends and hotspots in this field. The present study processes a macro-level literature analysis of antitumor nanocarriers and provides new perspectives and research directions for future development in cancer nanomedicine.

Nanoparticle Isolation from Biological Media for Protein Corona Analysis: The Impact of Incubation and Recovery Protocols on Nanoparticle Properties

Nanoparticles are increasingly implemented in biomedical applications, including the diagnosis and treatment of disease. When exposed to complex biological media, nanoparticles spontaneously interact with their surrounding environment, leading to the surface-adsorption of small and bio- macromolecules- termed the “corona”. Corona composition is governed by nanoparticle properties and incubation parameters. While the focus of most studies is on the protein signature of the nanoparticle corona, the impact of experimental protocols on nanoparticle size in the presence of complex biological media, and the impact of nanoparticle recovery from biological media has not yet been reported. Here using a non-degradable robust model, we show how centrifugation-resuspension protocols used for the isolation of nanoparticles from incubation media, incubation duration and shear flow conditions alter nanoparticle parameters including particle size, zeta potential and total protein content.Our results show significant changes in nanoparticle size following exposure to media containing protein under different flow conditions, which also altered the composition of surface-adsorbed proteins profiled by SDS-PAGE. Our in situ analysis of nanoparticle size in media containing protein using particle tracking analysis highlights that centrifugation-resuspension is disruptive to agglomerates that are spontaneously formed in protein containing media, highlighting the need for in situ analytical methods that do not alter the intermediates formed following nanoparticle exposure to biological media.Nanomedicines are mostly intended for parenteral administration, and our findings show that parameters such as shear flow can significantly alter nanoparticle physicochemical parameters. Overall, we show that the centrifugation-resuspension isolation of nanoparticles from media significantly alters particle parameters in addition to the overall protein composition of surface-adsorbed proteins. We recommend that nanoparticle characterization pipelines studying bio-nano interactions during early nanomedicine development consider biologically-relevant shear flow conditions and media composition that can significantly alter particle physical parameters and subsequent conclusions from these studies.

Electrospun short fibers: a new platform for cancer nanomedicine applications

With the continuous development of nanomaterials, nanofibers prepared by electrospinning have gradually occupied people’s vision because of their unique advantages, such as crisscross network and extracellular matrix-mimicking structure, high drug loading efficiency, and sustained release kinetics. Traditionally, electrospun fibers are mainly used as filter materials, wound dressings, and tissue engineering scaffolds, while their wide applications are limited to cancer nanomedicine applications due to their dense network structure. In recent years, two-dimensional fiber membranes have been transformed into short fibers that can be reconstructed to form fibrous rings or microspheres for cancer theranostics. Herein, this paper provides an overview of the recent advances in the design of electrospun short fibers that retain the advantages of nanofibers with good dispersibility for different nanomedicine applications, including cancer cell capture, cancer treatments, and cancer theranostics. The rational preparation of electrospun short fibers that are available to boost the development of nanomedicine is also discussed.

Electrospun short fibers: a new platform for cancer nanomedicine applications

With the continuous development of nanomaterials, nanofibers prepared by electrospinning have gradually occupied people’s vision because of their unique advantages, such as crisscross network and extracellular matrix-mimicking structure, high drug loading efficiency, and sustained release kinetics. Traditionally, electrospun fibers are mainly used as filter materials, wound dressings, and tissue engineering scaffolds, while their wide applications are limited to cancer nanomedicine applications due to their dense network structure. In recent years, two-dimensional fiber membranes have been transformed into short fibers that can be reconstructed to form fibrous rings or microspheres for cancer theranostics. Herein, this paper provides an overview of the recent advances in the design of electrospun short fibers that retain the advantages of nanofibers with good dispersibility for different nanomedicine applications, including cancer cell capture, cancer treatments, and cancer theranostics. The rational preparation of electrospun short fibers that are available to boost the development of nanomedicine is also discussed.

Citrus Flavonones into nanotechnology-based formulations to skin treatment

Introduction: Flavonones show potential application in the treatment of skin disorders, whose performance may be improved by using lipid and polymeric nanocarriers. In this review, a recent approach regarding nanocarriers containing either naringin, naringenin, hesperidin or hesperitin for skin application are discussed. Method: This review approaches the publications from the last 6 years about nanosystems containing Citrus flavonones for cutaneous applications. The articles were selected by searching in Scopus database for nanosystem containing either hesperidin, hesperitin, naringin or naringenin for cutaneous application, research articles written in English and published between 2018 and 2023, and reporting about skin penetration or biological evaluation. Results: Majority of reports employed lipid systems as nanocarriers. Naringenin was the most used flavonone. In relation to skin benefits, improved wound healing, atopic dermatitis treatment and stress oxidative-related diseases are highlighted. Despite the probable benefits, the development of plant-based nanomedicines is complex, which imposes limitations on the development of new pharmaceutical products. Further, the potential of flavonoids in the treatment of skin cancer has been shown. Conclusions: Lipid, polymeric and nanohybrid carriers are employed to deliver flavanones. Due to their antioxidant and anti-inflammatory activities, flavanones bear potential applications in the treatment of different skin disorders. Therefore, there is a promising application of flavanones to the improvement of human health, mainly with their loading into nanocarriers.

Force-Regulated Spontaneous Conformational Changes of Integrins α5β1 and αVβ3.

Integrins are cell surface nanosized receptors crucial for cell motility and mechanosensing of the extracellular environment, which are often targeted for the development of biomaterials and nanomedicines. As a key feature of integrins, their activity, structure and behavior are highly mechanosensitive, which are regulated by mechanical forces down to pico-Newton scale. Using single-molecule biomechanical approaches, we compared the force-modulated ectodomain bending/unbending conformational changes of two integrin species, α5β1 and αVβ3. It was found that the conformation of integrin α5β1 is determined by a threshold head-to-tail tension. By comparison, integrin αVβ3 exhibits bistability even without force and can spontaneously transition between the bent and extended conformations with an apparent transition time under a wide range of forces. Molecular dynamics simulations observed almost concurrent disruption of ∼2 hydrogen bonds during integrin α5β1 unbending, but consecutive disruption of ∼7 hydrogen bonds during integrin αVβ3 unbending. Accordingly, we constructed a canonical energy landscape for integrin α5β1 with a single energy well that traps the integrin in the bent state until sufficient force tilts the energy landscape to allow the conformational transition. In contrast, the energy landscape of integrin αVβ3 conformational changes was constructed with hexa-stable intermediate states and intermediate energy barriers that segregate the conformational change process into multiple small steps. Our study elucidates the different biomechanical inner workings of integrins α5β1 and αVβ3 at the submolecular level, helps understand their mechanosignaling processes and how their respective functions are facilitated by their distinctive mechanosensitivities, and provides useful design principles for the engineering of protein-based biomechanical nanomachines.