Special Issue on Advances in Nanomedicine

Nanomaterials are being increasingly used to develop new methods of disease diagnosis and treatment, thereby providing novel paradigms to break through the current limitations of medicine. However, there is still a long way toward the complete revolution for nanomedicine in the diagnosis and treatment of diseases. As nanoparticles are highly complex products and difficult to characterize, there are still many challenges. This special issue on Advances in Nanomedicine includes a series of topical reviews and original research articles that highlight the recent advances in diagnosis and therapy of nanomaterials.

Phototherapy including photothermal therapy (PTT) and photodynamic therapy (PDT), as non-invasive therapy approaches, have gained accumulated attention for cancer treatment in past years. PTT and PDT can generate local hyperthermia effects and reactive oxygen species (ROS) respectively, for tumor eradication. To improve the therapeutic performance while minimizing the reverse side effects of phototherapy, extensive efforts have been devoted to developing stimuli-activatable (e.g. pH, redox, ROS, enzyme, etc) nanomaterials for tumor-specific delivery/activation of the phototherapeutics. In this review, we first overviewed the recent advances of the engineered stimuli-responsive nanovectors for the phototherapy of cancer. We particularly summarized the progress of stimuli-activatable nanomaterials-based combinatory therapy strategies for augmenting the performance of phototherapy. We further discuss challenges for the clinical translation of nanomaterials-based phototherapy.

Fluorescence imaging technology in the second near-infrared bio-channel (NIR-II) has the advantages of low light scattering and weak autofluorescence. It can obtain high spatial resolution imaging in deeper biological tissues and realize accurate diagnosis in the lesion. As a new cancer treatment method, photothermal therapy has the characteristics of obvious curative effect and small side effects. However, the hydrophobicity and non-selectivity of many fluorescent materials, aggregation-induced fluorescence quenching, and other problems lead to undesirable imaging results. Here, we reviewed the structure of the NIR-II fluorescent molecules and these dyes whose fluorescence tail emission is in the NIR-II bio-channel, discussed in detail how to realize the redshift of the dye wavelength, including modifying the push–pull electron system, extending the conjugated chain, and forming J-aggregates and other methods. We also summarize some strategies to improve brightness, including responsiveness, targeting, adjustment of aggregation mode, and aggregation-induced emission effect, thereby improving the imaging performance and therapeutic effect of NIR-II fluorescent dyes.

Peptidic self-assembly provides a powerful method to build biomedical materials with integrated functions. In particular, pathological environment instructed peptidic supramolecular have gained great progress in treating various diseases. Typically, certain pathology related factors convert hydrophilic precursors to corresponding more hydrophobic motifs to assemble into supramolecular structures. Herein, we would like to review the recent progress of nanomedicines based on the development of instructed self-assembly against several specific disease models. Firstly we introduce the cancer instructed self-assembly. These assemblies have exhibited great inhibition efficacy, as well as enhanced imaging contrast, against cancer models both in vitro and in vivo. Then we discuss the infection instructed peptidic self-assembly. A number of different molecular designs have demonstrated the potential antibacterial application with satisfied efficiency for peptidic supramolecular assemblies. Further, we discuss the application of instructed peptidic self-assembly for other diseases including neurodegenerative disease and vaccine. The assemblies have succeeded in down-regulating abnormal Aβ aggregates and immunotherapy. In summary, the self-assembly precursors are typical two-component molecules with (1) a self-assembling motif and (2) a cleavable trigger responsive to the pathological environment. Upon cleavage, the self-assembly occurs selectively in pathological loci whose targeting capability is independent from active targeting. Bearing the novel targeting regime, we envision that the pathological conditions instructed peptidic self-assembly will lead a paradigm shift on biomedical materials.

With the improvement of living standards, cancer has become a great challenge around the world during last decades, meanwhile, abundant nanomaterials have been developed as drug delivery system (DDS) or cancer theranostic agents (CTAs) with their outstanding properties. However, low multifunctional efficiency and time-consuming synthesis limit their further applications. Nowadays, green chemistry, in particular, the concept of atom economy, has defined new criteria for the simplicity and efficient production of biomaterials for nanomedicine, which not only owns the property of spatio-temporal precision imaging, but also possess the ability to treat cancer. Interestingly, metal-organic framework (MOF) is an excellent example to meet the requirements behind this concept and has great potential for next-generation nanomedicine. In this review, we summarize our recent researches and inspiring progresses in designing DDS and CTA built from MOF, aiming to show the simplicity, control, and versatility, and provide views on the development of MOF-based nanomedicine in the future.

Nanomedicine has recently experienced unprecedented growth and development. However, the complexity of operations at the nanoscale introduces a layer of difficulty in the clinical translation of nanodrugs and biomedical nanotechnology. This problem is further exacerbated when engineering and optimizing nanomaterials for biomedical purposes. To navigate this issue, artificial intelligence (AI) algorithms have been applied for data analysis and inference, allowing for a more applicable understanding of the complex interaction amongst the abundant variables in a system involving the synthesis or use of nanomedicine. Here, we report on the current relationship and implications of nanomedicine and AI. Particularly, we explore AI as a tool for enabling nanomedicine in the context of nanodrug screening and development, brain–machine interfaces and nanotoxicology. We also report on the current state and future direction of nanomedicine and AI in cancer, diabetes, and neurological disorder therapy.

Nucleic acid-based gene therapy has recently made important progress toward clinical implementation, and holds tremendous promise for the treatment of some life-threatening diseases, such as cancer and inflammation. However, the on-demand delivery of nucleic acid therapeutics in target cells remains highly challenging. The development of delivery systems responsive to specific pathological cues of diseases is expected to offer promising alternatives for overcoming this problem. Among them, the reactive oxygen species (ROS)-responsive delivery systems, which in response to elevated ROS in cancer cells or activated inflammatory cells, can deliver nucleic acid therapeutics on-demand via ROS-induced structural and assembly behavior changes, constitute a promising approach for cancer and anti-inflammation therapies. In this short review, we briefly introduce the ROS-responsive chemical structures, ROS-induced release mechanisms and some representative examples to highlight the current progress in constructing ROS-responsive delivery systems. We aim to provide new insights into the rational design of on-demand gene delivery vectors.

Nanocarriers (NCs) for delivery anticancer therapeutics have been under development for decades. Although great progress has been achieved, the clinic translation is still in the infancy. The key challenge lies in the biological barriers which lie between the NCs and the target spots, including blood circulation, tumor penetration, cellular uptake, endo-/lysosomal escape, intracellular therapeutics release and organelle targeting. Each barrier has its own distinctive microenvironment and requires different surface charge. To address this challenge, charge-reversal polymeric NCs have been a hot topic, which are capable of overcoming each delivery barrier, by reversing their charges in response to certain biological stimuli in the tumor microenvironment. In this review, the triggering mechanisms of charge reversal, including pH, enzyme and redox approaches are summarized. Then the corresponding design principles of charge-reversal NCs for each delivery barrier are discussed. More importantly, the limitations and future prospects of charge-reversal NCs in clinical applications are proposed.

As a promising non-invasive treatment method, phototherapy has attracted extensive attention in the field of combined cancer therapy. Among various optical agents, organic ones have been considered as a promising clinical phototheranostic agent due to its high safety and non-toxic property. In addition, due to the clear structure, facile processability, organic optical agents can be easily endowed with multiple imaging and phototherapeutic functions, significantly simplifying the relatively complex system of imaging-guided combined cancer therapy. This review summarizes the recent research on organic optical agents in imaging-guided combined cancer therapy. The application of organic optical agents in a variety of combined cancer therapeutic modes guided by imaging are introduced respectively, including photodynamic and photothermal combined therapy, phototherapy-combined cancer chemotherapy, and phototherapy-combined cancer immunotherapy. Finally, the concluding remarks and the future prospects are discussed.

Osteoarthritis (OA) is a leading cause of chronic disability. It is a progressive disease, involving pathological changes to the entire joint, resulting in joint pain, stiffness, swelling, and loss of mobility. There is currently no disease-modifying pharmaceutical treatment for OA, and the treatments that do exist suffer from significant side effects. An increasing understanding of the molecular pathways involved in OA is leading to many potential drug targets. However, both current and new therapies can benefit from a targeted approach that delivers drugs selectively to joints at therapeutic concentrations, while limiting systemic exposure to the drugs. Delivery systems including hydrogels, liposomes, and various types of particles have been explored for intra-articular drug delivery. This review will describe progress over the past several years in the development of polymer-based particles for OA treatment, as well as their in vitro, in vivo, and clinical evaluation. Systems based on biopolymers such as polysaccharides and polypeptides, as well as synthetic polyesters, poly(ester amide)s, thermoresponsive polymers, poly(vinyl alcohol), amphiphilic polymers, and dendrimers will be described. We will discuss the role of particle size, biodegradability, and mechanical properties in the behavior of the particles in the joint, and the challenges to be addressed in future research.

Nanomaterials (NMs) have revolutionized multiple aspects of medicine by enabling novel sensing, diagnostic, and therapeutic approaches. Advancements in processing and fabrication have also allowed significant expansion in the applications of the major classes of NMs based on polymer, metal/metal oxide, carbon, liposome, or multi-scale macro-nano bulk materials. Concomitantly, concerns regarding the nanotoxicity and overall biocompatibility of NMs have been raised. These involve putative negative effects on both patients and those subjected to occupational exposure during manufacturing. In this review, we describe the current state of testing of NMs including those that are in clinical use, in clinical trials, or under development. We also discuss the cellular and molecular interactions that dictate their toxicity and biocompatibility. Specifically, we focus on the reciprocal interactions between NMs and host proteins, lipids, and sugars and how these induce responses in immune and other cell types leading to topical and/or systemic effects.

Nanozymes are nanomaterials with enzyme-like characteristics. As a new generation of artificial enzymes, nanozymes have the advantages of low cost, good stability, simple preparation, and easy storage, allowing them to overcome many of the limitations of natural enzymes in enzymatic therapy. Currently, most reported nanozymes exhibit oxidoreductase-like activities and can regulate redox balance in cells. Nanozymes with superoxide dismutase and catalase activity can be used to scavenge reactive oxygen species (ROS) for cell protection, while those with peroxidase and oxidase activity can generate ROS to kill harmful cells, such as tumor cells and bacteria. In this review, we summarize recent progress in nanozyme-based medicine for enzymatic therapy and highlight the opportunities and challenges in this field for future study.

Immunotherapy has emerged as a novel cancer treatment over the last decade, however, efficacious responses to mono-immunotherapy have only been achieved in a relatively small portion of patients whereas combinational immunotherapies often lead to concurrent side effects. It has been proved that the tumor microenvironment (TME) is responsible for tumor immune escape and the ultimate treatment failure. Recently, there has been remarkable progress in both the understanding of the TME and the applications of nanotechnological strategies, and reviewing the emerging immune-regulatory nanosystems may provide valuable information for specifically modulating the TME at different immune stages. In this review, we focus on comprehending the recently-proposed T-cell-based tumor classification and identifying the most promising targets for different tumor phenotypes, and then summarizing the nanotechnological strategies to best target corresponding immune-related factors. For future precise personalized immunotherapy, tailor-made TME modulation strategies conducted by well-designed nanosystems to alleviate the suppressive TME and then promote anti-tumor immune responses will significantly benefit the clinical outcomes of cancer patients.

The fast development of nanomedicine and nanobiotechnology has enabled the emerging of versatile therapeutic modalities with high therapeutic efficiency and biosafety, among which nanosonosensitizer-involved sonodynamic therapy (SDT) employs ultrasound (US) as the exogenous activation source for inducing the production of reactive oxygen species (ROS) and disease therapy. The chemoreactive nanosonosensitizers are the critical components participating in the SDT process, which generally determine the SDT efficiency and therapeutic outcome. Compared to the traditional and mostly explored organic sonosensitizers, the recently developed inorganic chemoreactive nanosonosensitizers feature the distinct high stability, multifunctionality and significantly different SDT mechanism. This review dominantly discusses and highlights two types of inorganic nanosensitizers in sonodynamic treatments of various diseases and their underlying therapeutic mechanism, including US-activated generation of electrons (e⁻) and holes (h⁺) for facilitating the following ROS production and delivery of organic molecular sonosensitizers. Especially, this review proposes four strategies aiming for augmenting the SDT efficiency on antitumor and antibacterial applications based on inorganic sonosensitizers, including defect engineering, novel metal coupling, increasing electric conductivity and alleviating tumor hypoxia. The encountered challenges and critical issues facing these inorganic nanosonosensitzers are also highlighted and discussed for advancing their clinical translations.

Iron-based nanomaterials have appeared in various cancer treatments owing to their promising functions and safety. Various sophisticated iron-based nanomaterials have been designed to exhibit great therapeutic effects through different strategies. Given the rapid progression, there is a great need to integrate the recent advances to learn about the latest innovation in this field. In this review, we classified the strategies of iron-based nanomaterials for cancer treatment into the following categories: immunotherapy, ferroptosis, magnetic hyperthermia and magneto-mechanical destruction. On the one hand, we discussed the underlining mechanism of iron-based nanomaterials in these therapies and applications; on the other hand, we analyzed the feasible combination of these applications and other therapies. Finally, the current challenges and expectation of iron-based nanomaterials in this field were highlighted.

The antitumor efficacy of various paclitaxel (PTX) and docetaxel (DTX) formulations in clinical applications is seriously affected by drug resistance. Cabazitaxel, a second-generation taxane, exhibits greater anticancer activity than PTX and DTX and has low affinity for the P-glycoprotein efflux pump because of its structure. Therefore, cabazitaxel has the potential to overcome taxane resistance. However, owing to the high systemic toxicity and hydrophobicity of cabazitaxel and the instability of its commercial preparation, Jevtana®, the clinical use of cabazitaxel is restricted to patients with metastatic castration-resistant prostate cancer who show progression after DTX-based chemotherapy. Nanomedicine is expected to overcome the limitations associated with cabazitaxel application and surmount taxane resistance. This review outlines the drug delivery systems of cabazitaxel published in recent years, summarizes the challenges faced in the development of cabazitaxel nanoformulations, and proposes strategies to overcome these challenges.

With a rapid advancement of nanotechnology and the close integration of disciplines, research on nanozymes (nanomaterials with enzyme-like activities), is becoming an expeditiously developing field. In recent years, platinum group element (PGE)-based (Pt, Pd, Ru, Rh, Ir, and Os) nanozymes developed successively, have not only promoted the research of nanozymes but also expanded the biomedical applications of nanomaterials. Generally speaking, PGE-based nanozymes process high catalytic efficiency, specific surface area, stability, and other physical/chemical properties, which benefit for their applications in biosensing, biological medicine, biomedical imaging, and environmental protection. This paper will introduce the research progress of PGE-based nanozymes including their synthesis, characterization, enzyme-like activities, stability, biocompatibility, toxicity, and applications for biological detection and clinical relevance. Our emphasis is put on unfolding the roles of PGE-based nanozymes in biomedical applications and how they overcome the limitations. Last but not least, trends and future perspectives of PGE-based nanozymes in biomedical applications are also provided.

Extracellular vesicles (EVs) are cell secretory native components with long-circulation, good biocompatibility, and physiologic barriers cross ability. EVs derived from different donor cells inherit varying characteristics and functions from their original cells and are favorable to serve as vectors for diagnosing and treating various diseases. However, EVs nanotheranostics are still in their infancy because of their limited accumulation at lesion sites and compromised therapy efficiency. Hence, engineering modification of EVs is usually needed to further enhance their stability, biological activity, and lesion-targeting capacity. Herein, we overview the characteristics of EVs from different sources, as well as the latest developments of surface engineering and cargo loading methods. We also focus especially on advances in EVs-based disease theranostics. At the end of the review, we predict the obstacles and prospects of the future clinical application of EVs.

Sonodynamic therapy (SDT) is a promising non-invasive therapeutic modality with an extensive application prospect. Due to the engineerable nature of nanotechnology, nanosensitizers with predominant advantages of increased SDT efficacy and targeting specificity have attracted more and more research recently. In this review, we introduce the current investigations of nanosonosensitizers and focus on the potential strategies on nanoparticles-assisted sonosensitizers to enhance SDT efficacy. We extensively discuss the biomedical applications of ultrasound activated nanosonosensitizers in SDT and theranostics.

Being a carbon-based hybrid, graphene-semiconductor composites have attracted considerable attention in recent decades owing to their potential features such as high photosensitivity, extended light absorption, and effective separation of charge carriers, thus have been regarded as a promising platform for environmental and biomedical applications, respectively. In this mini-review, we first summarized the recent advancements in the development of graphene-based semiconductor nanocomposites via sol–gel, solution mixing, in situ growth, hydrothermal, and solvothermal approaches, and then comprehensively reviewed their potential light activated cancer phototherapeutic applications. Finally, we rationally analyze the current challenges and new perspectives for the future development of more effective phototherapeutic nanoagents. We hope to offer enriched information to harvest the utmost fascinating properties of graphene as a platform to construct efficient graphene/semiconductor hybrids for cancer phototherapy.

Exosomes contain cargoes of proteins, lipids, micro-ribonucleic acids, and functional messenger RNAs, and they play a key role in cell-to-cell communication and hold valuable information about biological processes such as disease pathology. To harvest their potentials in disease diagnostics, prognostics, and therapeutics, exosome isolation is a crucial first step in providing pure and intact samples for both research and clinical purposes. Unfortunately, conventional methods for exosome separation suffer from low purity, low capture efficiency, long processing time, large sample volume requirement, the need for dedicated equipment and trained personnel, and high cost. In the last decade, microfluidic devices, especially those that incorporate nanostructures, have emerged as superior alternatives for exosome isolation and detection. In this review, we examine microfluidic platforms, dividing them into six categories based on their capture mechanisms: passive-structure-based affinity, immunomagnetic-based affinity, filtration, acoustofluidics, electrokinetics, and optofluidics. Here, we start out exploring the research and clinical needs that translate into important performance parameters for new exosome isolation designs. Then, we briefly introduce the conventional methods and discuss how their failure to meet those performance standards sparks an intense interest in microfluidic device innovations. The essence of this review is to lead an in-depth discussion on not only the technicality of those microfluidic platforms, but also their strengths and weaknesses with regards to the performance parameters set forth. To close the conversation, we call for the inclusion of exosome confirmation and contamination evaluation as part of future device development and performance assessment process, so that collectively, efforts towards microfluidics and nanotechnology for exosome isolation and analysis may soon see the light of real-world applications.

Optical imaging is a facile tool for visualizing biological processes and disease progression, but its image quality is largely limited by light-induced autofluorescence or background signals. To overcome this issue, low-background optical-imaging techniques including chemiluminescence imaging, afterglow imaging and photoacoustic imaging have been developed, based on their unique working mechanisms, which are: the detection of light emissions from chemical reactions, the cessation of light excitation before signal collection, and the detection of ultrasonic signals instead of light signals, respectively. Stimuli-responsive probes are highly desirable for improved imaging results since they can significantly reduce surrounding interference signals. Reactive oxygen species (ROS), which are closely implicated in a series of diseases such as cancer and inflammation, are frequently employed as initiators for responsive agents to selectively change the imaging signal. Thus, ROS-responsive agents incorporated into low-background imaging techniques can achieve a more promising imaging quality. In this review, recent advances in ROS-responsive probes for low-background optical-imaging techniques are summarized. Moreover, the approaches to improving the sensitivity of probes and tissue penetration depth are discussed in detail. In particular, we highlight the reaction mechanisms between the probes and ROS, revealing the potential for low-background optical imaging.

Pharmacotherapies for brain disorders are generally faced with obstacles from the blood-brain barrier (BBB). There are a variety of drug delivery systems that have been put forward to cross or bypass the BBB with the access to the central nervous system. Brain drug delivery systems have benefited greatly from the development of nanocarriers, including lipids, polymers and inorganic materials. Consequently, various kinds of brain drug delivery nano-systems have been established, such as liposomes, polymeric nanoparticles (PNPs), nanomicelles, nanohydrogels, dendrimers, mesoporous silica nanoparticles and magnetic iron oxide nanoparticles. The characteristics of their carriers and preparations usually differ from each other, as well as their transportation mechanisms into intracerebral lesions. In this review, different types of brain drug delivery nanocarriers are classified and summarized, especially their significant achievements, to present several recommendations and directions for future strategies of cerebral delivery.

Inhalation delivery of liposomal drugs has distinct advantages for the treatment of pulmonary diseases. Inhalable liposomes of several drugs are currently undergoing clinical trials for a range of indications in the lungs. Herein, general principles of pulmonary delivery as well as the clinical development of inhalable liposomal drugs are reviewed.

Mounting evidence shows the great promise of nanoparticle drug delivery systems (nano-DDSs) to improve delivery efficiency and reduce off-target adverse effects. By tracking drug delivery and distribution, monitoring nanoparticle degradation and drug release, aiding and optimizing treatment planning, and directing the design of more robust nano-DDSs, image guidance has become a vital component of nanomedicine. Recently, chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) has emerged as an attempting imaging method for achieving image-guided drug delivery. One of the unbeatable advantages of CEST MRI is its ability to detect diamagnetic compounds that cannot be detected using conventional MRI methods, making a broad spectrum of bioorganic agents, natural compounds, even nano-carriers directly MRI detectable in a high-spatial-resolution manner. To date, CEST MRI has become a versatile and powerful imaging technology for non-invasive in vivo tracking of nanoparticles and their loaded drugs. In this review, we will provide a concise overview of different forms of recently developed, CEST MRI trackable nano-DDSs, including liposomes, polymeric nanoparticles, self-assembled drug-based nanoparticles, and carbon dots. The potential applications and future perspectives will also be discussed.

Multiple sclerosis (MS) is a neurodegenerative disease with a high morbidity and disease burden. It is characterized by the loss of the myelin sheath, resulting in the disruption of neuron electrical signal transmissions and sensory and motor ability deficits. The diagnosis of MS is crucial to its management, but the diagnostic sensitivity and specificity are always a challenge. To overcome this challenge, nanomedicines have recently been employed to aid the diagnosis of MS with an improved diagnostic efficacy. Advances in nanomedicine-based contrast agents in magnetic resonance imaging scanning of MS lesions, and nanomedicine-derived sensors for detecting biomarkers in the cerebrospinal fluid biopsy, or analyzing the composition of exhaled breath gas, have demonstrated the potential of using nanomedicines in the accurate diagnosis of MS. This review aims to provide an overview of recent advances in the application of nanomedicines for the diagnosis of MS and concludes with perspectives of using nanomedicines for the development of safe and effective MS diagnostic nanotools.

In the past few decades, various vanadium compounds have displayed potential in cancer treatment. However, fast clearness in the body and possible toxicity of vanadium compounds has hindered their further development. Vanadium-based nanomaterials not only overcome these limitations, but take advantage of the internal properties of vanadium in photics and magnetics, which enable them as a multimodal platform for cancer diagnosis and treatment. In this paper, we first introduced the basic biological and pharmacological functions of vanadium compounds in treating cancer. Then, the synthesis routes of three vanadium-based nanomaterials were discussed, including vanadium oxides, 2D vanadium sulfides, carbides and nitrides: V_mX_n (X = S, C, N) and water-insoluble vanadium salts. Finally, we highlighted the applications of these vanadium-based nanomaterials as tumor therapeutic and diagnostic agents.

Cellular metabolites play a crucial role in promoting and regulating cellular activities, but it has been difficult to monitor these cellular metabolites in living cells and in real time. Over the past decades, iterative development and improvements of fluorescent probes have been made, resulting in the effective monitoring of metabolites. In this review, we highlight recent progress in the use of fluorescent probes for tracking some key metabolites, such as adenosine triphosphate, cyclic adenosine monophosphate, cyclic guanosine 5'-monophosphate, Nicotinamide adenine dinucleotide (NADH), reactive oxygen species, sugar, carbon monoxide, and nitric oxide for both whole cell and subcellular imaging.

Single-mode magnetic resonance imaging (MRI) contrast agents (CAs) in clinical settings are easily disturbed by calcification, bleeding, and adipose signals, which result in inaccurate diagnoses. In this study, we developed a highly efficient T₁–T₂ dual-mode MRI CA using an ultra-small gadolinium oxide-decorated magnetic iron oxide nanocrystal (GMIO). The gadolinium element could effectively alter the magnetic properties of the GMIO from soft-ferromagnetism to superparamagnetism. In addition, when the Gd/Fe ratio was 15% (designated as GMIO-2), the GMIO-2 possessed the best superparamagnetism and highest magnetism. Subsequently, T₁ and T₂ values of GMIO-2 were measured through a series of turbo spin-echo images and then multi-spin echo sequence, respectively. Based on this, T₁ and T₂ relaxivities of GMIO-2 were calculated and were the highest (r₁: 1.306 m M⁻¹ s⁻¹ and r₂: 234.5 m M⁻¹ s⁻¹) when compared to other groups. The cytotoxicity of GMIO-2 was negligible under a wide range of dosages, thus exhibiting excellent cell biocompatibility. Moreover, GMIO-2 could quickly diffuse into cells, leading to its effective accumulation. The systemic delivery of GMIO-2 resulted in an excellent T₁–T₂ dual-mode MRI contrast effect in kidneys, which is expected to improve the diagnosis of kidney lesions. Therefore, this work provides a promising candidate for the development of a T₁–T₂ dual-mode MRI CA.

An efficient long-term intracellular growth factor release system in simulated microgravity for osteogenic differentiation was prepared based on polylactic acid (PLA) and polyhydroxyalkanoate (PHA) nanoparticles (NPs) for loading of bone morphogenetic protein 2 (BMP2) and bone morphogenetic protein 7 (BMP7) (defined as sB2-PLA-NPs and sB7-PHA-NPs), respectively, associated with osteogenic differentiation of human adipose derived stem cells (hADSCs). On account of soybean lecithin (SL) as biosurfactants, sB2-PLA-NPs and sB7-PHA-NPs had a high encapsulation efficiency (>80%) of BMPs and uniform small size (<100 nm), and showed a different slow-release to provide BMP2 in early stage and BMP7 in late stages of osteogenic differentiation within 20 d, due to degradation rate of PLA and PHA in cells. After uptake into hADSCs, by comparison with single sB2-PLA-NPs or sB7-PHA-NPs, the Mixture NPs compound of sB2-PLA-NP and sB7-PHA-NP with a mass ratio of 1:1, can well-promote ALP activity, expression of OPN and upregulated related osteo-genes. Directed osteo-differentiation of mixture NPs was similar to result of sustained free-BMP2 and BMP7-supplying (sFree-B2&B7) in simulated microgravity, which demonstrated the reliability and stability of Mixture NPs as a long-term osteogenic differentiation system in space medicine and biology in future.

In this work, we reported an upgraded mussel-inspired strategy for surface bioengineering of osteoimplants by combination of mussel adhesion and bioorthogonal click chemistry. The main idea of this strategy is a mussel-inspired synthetic peptide containing multiple 3,4-dihydroxy-L-phenylalanine (DOPA) units and a dibenzocyclooctyne (DBCO) terminal (DOPA-DBCO). According to the mussel adhesion mechanism, the DOPA-DBCO peptide could stably adhere onto a variety of material surface, leaving the residual DBCO groups on the surface. Then, the DBCO residues could be employed for a second-step bioorthogonal conjugation with azide-capping biomolecules through bioorthogonal click chemistry, finally leading to the biomodified surfaces. To demonstrate the generality of our strategy for surface biomodification of diversified orthopaedic materials including metallic and polymeric substrates, we here conceptually conjugated some typical azide-capping biomolecules on both metal and polymeric surfaces. The results definitely verified the feasibility for engineering of functional surfaces with some essential requirements of osteoimplants, for example, the ability to facilitate cell adhesion, suppress bacterial infection, and promote osteogenesis. In a word, this study indicated that our novel surface strategy would show broad applicability for diverse osteoimplants and in different biological scenarios. We can also image that the molecular specificity of bioorthogonal conjugation and the universality of mussel adhesion mechanism may jointly provide a versatile surface bioengineering method for a wider range of biomedical implants.