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The considerable development of carrier-free nanodrugs has been achieved due to their high drug-loading capability, simple preparation method, and offering “all-in-one” functional platform features. However, the native defects of carrier-free nanodrugs limit their delivery and release behavior throughout the in vivo journey, which significantly compromise the therapeutic efficacy and hinder their further development in cancer treatment. In this review, we summarized and discussed the recent strategies to enhance drug delivery and release of carrier-free nanodrugs for improved cancer therapy, including optimizing the intrinsic physicochemical properties and external modification. Finally, the corresponding challenges that carrier-free nanodrugs faced are discussed and the future perspectives for its application are presented. We hope this review will provide constructive information for the rational design of more effective carrier-free nanodrugs to advance therapeutic treatment., Graphical abstract Great enhancement of carrier-free nanodrugs has been achieved to overcome the defects during the in vivo journey. This review has systemically summarized the recent strategies to enhance drug delivery and release of carrier-free nanodrugs, including optimizing the intrinsic physicochemical properties and external modification.Image 1, Highlights • Recent progresses on carrier-free nanodrugs for enhancing drug delivery and release are summarized. • Strategies of optimizing the intrinsic physicochemical properties and external modification are summarized. • Future perspectives and challenges of carrier-free nanodrugs are discussed.

Heart failure (HF) has continued to be a leading cause of morbidity and mortality worldwide. Nanomedicine, which can deliver therapeutic drugs/biomolecules specifically to damaged myocardium and overcome the limitations of conventional therapies, shows great potential in the treatment of HF. Although a number of preclinical studies of cardiac nanoformulations have been published, targeted nanomedicine for HF is yet to be applied in clinical practice. Therefore, it is meaningful to sum up past experiences and deepen the understanding of nanomedicine and HF. In this review, we first emphasized the key biological barriers to cardiac nanomedicine that hinder its targeting effect. Since the rational design of nanoparticles should take into account the specific characteristics of HF, we then summarized the key pathophysiological changes of HF to provide a clear understanding on HF, as well as the latest examples of nanotechnology-based delivery strategies for different pathophysiological characteristics. Finally, the major challenges are discussed in detail, aiming to provide guidance for future development of cardiac nanomedicine.

Bone metastases have gradually been recognized as common metastases that affect patient quality of life and survival due to the increased incidence of primary tumors. However, there is still a lack of effective clinical treatment methods for bone metastases because of their particularity and complexity. Nanomedicine provides a new strategy for the treatment of bone metastases and shows great therapeutic potential. Thus, it is important to review the latest nanomedicine treatments for bone metastases.This review introduces the mechanistic relationships of bone metastases and summarizes nanotechnology-based treatments of bone metastases according to targeting strategies.As we start to understand the mechanisms that enable bone metastases, we can better develop nanomedicine treatments. However, many of the mechanisms behind bone metastasis remain unclear. The application of nanomedicine shows promising anti-bone metastasis efficacy and helps to explore the pathogenesis of bone metastases. The optimized construction of nanomedicine according to bone metastatic properties is crucial to ensure the desired anti-bone metastasis efficacy and good biosafety. Therefore, the transition from bench to bedside still requires continued exploration.

Nanoparticles have shown great potential in tumor drug delivery. However, the accumulation and deep penetration behaviors of nanoparticles still need to be improved because of the barrier of tumor microenvironment. Recent days, intelligent aggregatable or shrinkable nanoparticles exhibit both good accumulation and deep penetration, providing the prospect for improved antitumor efficacy. This Spotlight first gives a concise introduction of the "size dilemma" in tumor accumulation and deep penetration and then goes in detail on our own contribution to the field of size aggregation and size shrinkage strategies. Also, we introduce the combination therapy of the size change strategy and other treatments, and the synergistic effect significantly improves the antitumor efficacy. In the end, we discuss the future directions for the potential applications.

Recent days, aggregatable nanoparticles, which can specifically respond to certain stimulus, have shown great potential in tumor-targeted drug delivery with prolonged retention and deeper penetration. In this review, we summarize recent advances in design of aggregatable nanoparticles by different stimuli. Internal (pH and enzyme) and external (light, temperature and ROS) stimuli are introduced for a comprehensive description. Moreover, the aggregated nanoparticles usually exhibit photothermal, photoacoustic, PET and enhanced MRI contrast, which is also described. In the end, we discuss about the potential applications and challenges for the future clinical translation.

In the past decade, nanoscale metal-organic frameworks (nMOFs) have drawn a great attention due to their high porosity, wide range of pore shapes, tunable frameworks and relatively low toxic. With the development of nanotechnology, many researchers studied the synthesis, characterization, functionalization and biotoxicity of nMOFs, and a more thorough understanding was developed about numerous nMOFs as promising platforms for biomedical applications. This review highlights the up-to-date progress of nMOFs related to their bio-applications such as drug delivery, bioimaging, biosensing and biocatalysis, and the common surface modification methods were classified into four categories: covalent post-synthetically modification, coordinative post-synthetically modification, noncovalent post-synthetically modification and modification on the external surface. At the same time, the challenges and perspectives of nMOFs were discussed as well.

Nanogel-based nanoplatforms have become a tremendously promising system of drug delivery. Nanogels constructed by chemical crosslinking or physical self-assembly exhibit the ability to encapsulate hydrophilic or hydrophobic therapeutics, including but not limited to small-molecule compounds and proteins, DNA/RNA sequences, and even ultrasmall nanoparticles, within their 3D polymer network. The nanosized nature of the carriers endows them with a specific surface area and inner space, increasing the stability of loaded drugs and prolonging their circulation time. Reactions or the cleavage of chemical bonds in the structure of drug-loaded nanogels have been shown to trigger the controlled or sustained drug release. Through the design of specific chemical structures and different methods of production, nanogels can realize diverse responsiveness (temperature-sensitive, pH-sensitive and redox-sensitive), and enable the stimuli-responsive release of drugs in the microenvironments of various diseases. To improve therapeutic outcomes and increase the precision of therapy, nanogels can be modified by specific ligands to achieve active targeting and enhance the drug accumulation in disease sites. Moreover, the biomembrane-camouflaged nanogels exhibit additional intelligent targeted delivery features. Consequently, the targeted delivery of therapeutic agents, as well as the combinational therapy strategy, result in the improved efficacy of disease treatments, though the introduction of a multifunctional nanogel-based drug delivery system.

Background Nanotechnology based diagnostic and therapeutic approaches have attracted great interest in oncology over the last few years. Especially gold (Au)-based nanoformulations have gained a lot of attention in cancer detection, therapy and monitoring of outcome. The current report provides a summary of methods how to prepare different types of synthetic gold nanoformulations and their potential applications in boosting photothermal and photodynamic tumor therapies and in radiosensitization. Method A comprehensive review of the literature on the current status of gold nanoparticles preparation methods and their application for cancer therapy was performed. Results The intrinsic properties of the nanoparticles such as shape, size, electronic, optical, physicochemical and surface plasmon resonance (SPR) features could be precisely adjusted through various synthetic approaches depending on the further application of particles in biomedicine. According to various reports, gold nanoformulations have shown promising potential as adjuvants for photothermal and photodynamic therapies and as radiosensitizers for radiation therapy. Conclusion Synthetic development of gold nanoformulations became an important strategy in nanomedicine. Nanocomplexes demonstrated a therapeutic potential and could be translated into clinical strategies for cancer therapy.

Owing to the convenient and visual advantages, dye mapping agents are the most popular lymph tracing agents in the current clinic practices. However, limit tissue penetration always leads to hardly detect deeper lymph nodes (LNs), such as regional lymph nodes (RLNs). Therefore, exploring multimodal nanotheranostic agents for diagnosis and treatment of metastatic LNs are desired. In this study, polydopamine-encapsulated gadolinium-loaded multi-walled carbon nanotube (MWCNT-Gd@PDA) were strategically designed for dual-modality mapping guided photothermal therapy (PTT) by positive signal of magnetic resonance imaging (MRI) as well as deep black of the nanomaterials providing visual information. PDA, with excellent biocompatibility and biodegradability, can be easily deposited on many kinds of inorganic and organic materials to prepare functional materials. In order to prevent gadolinium ion escaping from the MWCNT, PDA shell was coated on the surface of MWCNT-Gd. Thus, the prepared MWCNT-Gd@PDA nanomaterials were lack of inherent biological toxicity. More importantly, under the guidance of dual-modality mapping, we demonstrated that primary tumors and RLNs could be simultaneously and effectively ablated by near-infrared irradiation to acquire the radical photothermal dissection. The results showed that our nanosystem possessed the precise spatial-temporal selectivity in comparison with conventional surgery and T2-MRI guided PTT.

Carbonaceous dots (CDs) are superior nanomaterials owing to their promising luminescence properties and good biocompatibility. However, most CDs have relatively short excitation/emission, which restrict their application in bioimaging. In this study, a simple one-step procedure was developed for synthesis of melanin-originated CDs (MNPs). The MNPs showed two long red shift emissions at 570 nm and 645 nm with broad absorptions from 200 nm to 400 nm and 500 nm to 700 nm, suggesting the great potential of MNPs in bioimaging. Besides, several experiments indicated that MNPs possessed good serum stability and well blood compatibility. In vitro, MNPs could be taken up by C6 cell in a concentration- and time-dependent manner with endosomes involved. In conclusion, MNPs were prepared using a simple one-step method with unique optical and good biological properties and could be used for bioimaging.

Cancer is still one of the most serious diseases with threats to health and life. Although some advances have been made in targeting delivery of antitumor drugs over the past number of years, there are still many problems needing to be solved, such as poor efficacy and high systemic toxicity. Micro/nanomotors capable of self-propulsion in fluid provide promising platforms for improving the efficiency of tumor delivery. Herein, the recent progress in micro/nanomotors for tumor targeting delivery and therapy is reviewed, with special focus on the contributions of micro/nanomotors to the different stages of tumor targeting delivery as well as the combination therapy by micro/nanomotors. The present limitations and future directions are also put forward for further development.

Due to the high morbidity and mortality of cancer, it has become an urgent matter to develop an effective and a safe treatment strategy. Nanoparticles (NP) based drug delivery systems have gained much attention nowadays but they faced a paradoxical issue in delivering drugs into tumors: NP with large size were characterized with weak tumor penetration, meanwhile NP with small size resulted in poor tumor retention. To solve this problem, we proposed a multistage drug delivery system which could intelligently shrink its size from large size to small size in the presence of matrix metalloproteinase-2 (MMP-2) which were highly expressed in tumor tissues, therefore the multistage system could benefit from its large size for better retention effect in tumor and then shrunk to small size to contribute to better penetration efficiency. The multistage drug delivery system, RGD-DOX-DGL-GNP, was constructed by 155.4nm gelatin NP core (the substrate of MMP-2) and surface decorated with doxorubicin (DOX) and RGD peptide conjugated dendritic poly-l-lysine (DGL, 34.3nm in diameter). In vitro, the size of multistage NP could effectively shrink in the presence of MMP-2. Thus, the RGD-DOX-DGL-GNP could penetrate deep into tumor spheroids. In vivo, this multistage drug delivery system showed higher tumor retention and deeper penetration than both DOX-DGL and DOX-GNP. Consequently, RGD-DOX-DGL-GNP successfully combined the advantages of dendrimers and GNP in vivo, resulting in an outstanding anti-tumor effect. In conclusion, the multistage drug delivery system could intelligently shrink from large size to small size in the tumor microenvironment and displayed better retention and penetration efficiency, making it an impressing system for cancer treatment.

A new type of carbon dots (CD-Asp) with targeting function toward brain cancer glioma was synthesized via a straightforward pyrolysis route by using D-glucose and L-aspartic acid as starting materials. The as-prepared CD-Asp exhibits not only excellent biocompatibility and tunable full-color emission, but also significant capability of targeting C6 glioma cells without the aid of any extra targeting molecules. In vivo fluorescence images showed high-contrast biodistribution of CD-Asp 15 min after tail vein injection. A much stronger fluorescent signal was detected in the glioma site than that in normal brain, indicating their ability to freely penetrate the blood-brain barrier and precisely targeting glioma tissue. However, its counterparts, the CDs synthesized from D-glucose (CD-G), L-asparic acid (CD-A), or D-glucose and L-glutamic acid (CD-Glu) have no or low selectivity for glioma. Therefore, CD-Asp could act as a fluorescence imaging and targeting agent for noninvasive glioma diagnosis. This work highlights the potential application of CDs for constructing an intelligent nanomedicine with integration of diagnostic, targeting, and therapeutic functions.

Fluorescent carbonaceous dots (CDs) have attracted much attention due to their unique properties. However, their application in non-invasive imaging of diseased tissues was restricted by the short excitation/emission wavelength and the poor targeting efficiency of CDs. In this study, CDs were prepared from sucrose and glutamic acid with a particle size of 57.5 nm. An obvious emission could be observed at 600 nm to 700 nm when excited at around 500 nm. This property enabled CDs with a capacity for deep tissue imaging with low background adsorption. RGD, a ligand which could target most tumor and neovasculature cells, was anchored onto CDs after PEGylation. The product, RGD–PEG–CDs could accumulate in MCF-7/ADR xenografts at high intensity, which was 1.65-fold higher than that of PEG–CDs. Furthermore, RGD–PEG–CDs showed good colocalization with neovasculature. Thus, RGD–PEG–CDs could be used for non-invasive MCF-7/ADR tumor imaging. CDs functionalized with other ligands may also be used as a non-invasive probe for many kinds of tumor imaging.

Targeting delivery and deep penetration have been attracting tremendous attention in triple-negative breast cancer (TNBC) theranostics. Herein, we reported a novel multistage system (G-AuNPs-DOX-RRGD) with an active targeting effect and size-changeable property to inhibit tumor growth and metastasis in 4T1 xenograft bearing mice. The system was constructed through fabricating small-size gold nanoparticles (AuNPs) onto matrix metalloproteinase-2 (MMP-2) degradable gelatin nanoparticles (GNPs). Doxorubicin (DOX) was tethered onto AuNPs via a pH sensitive hydrazone bond, and RRGD, a tandem peptide of RGD and octarginine, was surface-decorated onto the system to improve its tumor targeting efficiency. In vitro, the G-AuNPs-DOX-RRGD could shrink from 185.9 nm to 71.2 nm after 24 h incubation with MMP-2 and the DOX was released in a pH-dependent manner. Tumor spheroid penetration and collagen diffusion demonstrated G-AuNPs-DOX-RRGD possessed best penetrating efficiency. In vivo, the G-AuNPs-DOX-RRGD actively targeted to the 4T1 tumor and then penetrated through the interstitial matrix, resulted in enhanced accumulation in the deep tumor region. Therefore, the G-AuNPs-DOX-RRGD could approach excellent anti-tumor capacity owing to the synergistic effect of RRGD and the size-changeable property.

Angiopep-2 modified and doxorubicin loaded carbonaceous nanodots (AN-PEG-DOX-CDs) were synthesized for glioma cell targeting, delivery and redox-responsive release of doxorubicin. Our results provided the possibility of using CDs to construct smart drug delivery systems.

Glioblastoma (GBM), one of the most lethal cancers, remains as a hard task to handle. The major hurdle of nanostructured therapeutic agents comes from the limited retention at the GBM site and poor selectivity. In this study, we reported dual-functional gold nanoparticles (AuNPs) to figure out the biological barrier and improve their accumulation in GBM. The nanoparticles, AuNP-A&C-R, were composed of two functional particles: one was Ala-Ala-Asn-Cys-Asp (AK) and R8-RGD-comodified AuNPs (AuNP-AK-R) and the other was 2-cyano-6-amino-benzothiazole and R8-RGD-comodified AuNPs (AuNP-CABT-R). AuNP-A&C-R could aggregate in the presence of legumain, resulting in a size increase from 41.4 ± 0.6 to 172.9 ± 10.2 nm after 8 h incubation. After entering the circulatory system, AuNP-A&C-R actively targeted the integrin αvβ3 receptor on blood–brain barrier (BBB), mediated transcytosis of particles across BBB, and then targeted the receptor on the GBM cells. Once AuNP-A&C-R entered into GBM, they formed further aggregat...

Liposomes are widely used as drug delivery systems and several liposome-based nanomedicines have been approved for clinical use. Cell penetrating peptides (CPPs) have been decorated onto nanoparticulated vesicle such as liposomes to further improve the intracellular delivery efficiency. However, the poor selectivity of CPPs hindered their application, especially in the in vivo application. To resolve this issue, several strategies have been developed, including shielding and environment-triggered deshielding of CPPs as well as designing of environment-responsive CPPs and specific- targeting CPPs and last but not least, combination strategy. In this review, the abovementioned strategies were discussed.

A practical and effective strategy for loading hydrophobic anticancer agents within the inside and outside oleic acid layer of Rubik-like magnetic nanoassemblies (MNAs) is established. In this strategy, four individual oleic acid-capped iron oxide nanocubes and dioleate-modified polyethylene glycol are assembled into cluster with high drug loading capability, high magnetism, as well as rapid and extended release behavior. After loading model drug paclitaxel (PTX), PTX-MNAs show greater antitumor activity both in vitro cell culture and in vivo animal trials compared with the same dose of free PTX (Taxol). With high uptake by tumor cells, MNAs exhibit in tumor imaging by magnetic resonance imaging. These outstanding properties are largely due to the drug delivery systems that take high drug-loading capability and high magnetism into consideration in a nano-dimension for maximizing the nanotheranostic functions and minimizing the toxic side effects. In summary, the Rubik-like magnetic nanoassemblies may have the potential to realize “all-in-one” nanotheranostic strategy to detect, diagnose, treat, and monitor tumors and therapeutic response in further pre-clinical and clinical studies.

Carbonaceous dots exhibit increasing applications in diagnosis and drug delivery due to excellent photostability and biocompatibility properties. However, relative short excitation and emission of melanin carbonaceous dots (MCDs) limit the applicability in fluorescence bioimaging. Furthermore, the generally poor spatial resolution of fluorescence imaging limits potential in vivo applications. Due to a variety of beneficial properties, in this study, MCDs were prepared exhibiting great potential in fluorescence and photoacoustic dual-mode bioimaging. The MCDs exhibited a long excitation peak at 615 nm and emission peak at 650 nm, further highlighting the applicability in fluorescence imaging, while the absorbance peak at 633 nm renders MCDs suitable for photoacoustic imaging. In vivo, the photoacoustic signal of MCDs was linearly correlated with the concentration of MCDs. Moreover, the MCDs were shown to be taken up into triple negative breast cancer cell line 4T1 in both a time- and concentration-dependent manner. In vivo fluorescence and photoacoustic imaging of subcutaneous 4T1 tumor demonstrated that MCDs could passively target triple negative breast cancer tissue by enhanced permeability and retention effects and may therefore be used for tumor dual-mode imaging. Furthermore, fluorescence distribution in tissue slices suggested that MCDs may distribute in 4T1 tumor with high efficacy. In conclusion, the MCDs studied offer potential application in fluorescence and photoacoustic dual-mode imaging.

Nanomaterials and nanomedicines have been widely used and brain exposure is a critical concern. Neurotoxicity is more or less observed when brain is exposed to various kinds of nanomaterials and nanomedicines. How to reduce the neurotoxicity is an interesting and important topic that emerged from the application of nanomaterials and nanomedicines. Although the related studies are limited, in this chapter, we try to discuss the potential strategies to reduce the neurotoxicity.

The restriction of the blood–brain barrier poses a great challenge to manage central nervous system disorders. Nanomaterials showed promising application in the delivery of various kinds of drugs to the brain, including small chemical drugs, peptides and proteins, and genes. In this chapter, we review the most widely used nanomaterials in brain targeting delivery, such as natural materials, anionic and neutral polymers, cationic polymers, dendrimers, metal-based nanoparticles, and carbon-based nanomaterials. We also describe the strategies to modify these nanomaterials to facilitate brain targeting delivery and the treatment outcomes using these strategies.

Despite the great achievements that nanomedicines have obtained so far, deep penetration of nanomedicines into tumors is still a major challenge in tumor treatment. The enhanced permeability and retention (EPR) effect was the main theoretical foundation for using nanomedicines to treat solid tumor. However, the antitumor efficiency is modest because the tumor is heterogeneous, with dense collagen matrix, abnormal tumor vasculature, and lymphatic system. Nanomedicines could only passively accumulate near leaky site of tumor vessels, and they cannot reach the deep region of tumor. To enhance further the tumor penetration efficiency, we developed a novel strategy of coadministering cell-homing penetration peptide iRGD with size-shrinkable and tumor-microenvironment-responsive multistage system (DOX-AuNPs-GNPs) to overcome these barriers. First, iRGD could specifically increase the permeability of tumor vascular and tumor tissue, leading to more DOX-AuNPs-GNPs leaking out from tumor vasculature. Second, the multistage system passively accumulated in tumor tissue and shrank from 131.1 to 46.6 nm to reach the deep region of tumor. In vitro, coadministering iRGD with DOX-AuNPs-GNPs showed higher cellular uptake and apoptosis ratio. In vivo, coadministering iRGD with DOX-AuNPs-GNPs presented higher penetration and accumulation in tumor than giving DOX-AuNPs-GNPs alone, leading to the best antitumor efficiency in 4T1 tumor-bearing mouse model.

Fluorescent carbonaceous nanodots (CDs) have attracted much attention due to their unique properties. However, their application in noninvasive imaging of diseased tissues was restricted by the short excitation/emission wavelengths and the low diseased tissue accumulation efficiency. In this study, CDs were prepared from glucose and glutamic acid with a particle size of 4 nm. Obvious emission could be observed at 600 to 700 nm when CDs were excited at around 500 nm. This property enabled CDs with capacity for deep tissue imaging with low background adsorption. Angiopep-2, a ligand which could target glioma cells, was anchored onto CDs after PEGylation. The product, An-PEG-CDs, could target C6 glioma cells with higher intensity than PEGylated CDs (PEG-CDs), and endosomes were involved in the uptake process. In vivo, An-PEG-CDs could accumulate in the glioma site at higher intensity, as the glioma/normal brain ratio for An-PEG-CDs was 1.73. The targeting effect of An-PEG-CDs was further demonstrated by receptor staining, which showed An-PEG-CDs colocalized well with the receptors expressed in glioma. In conclusion, An-PEG-CDs could be successfully used for noninvasive glioma imaging.

Fluorescent carbonaceous nanospheres (CDs) have generated much excitement in bioimaging because of their impressive fluorescent properties and good biocompatibility. In this study, we evaluated the potential application of CDs in noninvasive brain imaging. A new kind of CDs was prepared by a heat treating method using glutamic acid and glucose as the precursors. The hydrated diameter and zeta potential of CDs were 101.1 nm (PDI = 0.110) and −22.4 mV respectively. Palpable emission spectrum could be observed from 400 nm to 600 nm when excited at corresponding wavelength, suggesting CDs could be used as a noninvasive bio-probe for in vivo imaging. Additionally, several experiments indicated that CDs possess good serum stability and hemocompatibility with low cytotoxicity. In vitro, the CDs could be efficiently taken up by bEnd.3 cells in a concentration- and time-dependent manner. In vivo, CDs could be used for noninvasive brain imaging due to its high accumulation in brain region, which was demonstrated by in vivo imaging and ex vivo tissue imaging. Moreover, the fluorescent distribution in tissue slice showed CDs accumulated in brain with high intensity. In conclusion, CDs were prepared using a simple one-step method with unique optical and good biological properties and could be used for noninvasive brain imaging.

Gliomas are hard to treat because of the two barriers involved: the blood-brain barrier and blood-tumor barrier. In this study, a dual-targeting ligand, angiopep-2, and an activatable cell-penetrating peptide (ACP) were functionalized onto nanoparticles for glioma-targeting delivery. The ACP was constructed by conjugating RRRRRRRR (R8) with EEEEEEEE through a matrix metalloproteinase-2 (MMP-2)-sensitive linker. ACP modification effectively enhanced the C6 cellular uptake because of the high expression of MMP-2 on C6 cells. The uptake was inhibited by batimastat, an MMP-2 inhibitor, suggesting that the cell-penetrating property of the ACP was activated by MMP-2. By combining the dual-targeting delivery effect of angiopep-2 and activatable cell-penetrating property of the ACP, the dual-modified nanoparticles (AnACNPs) displayed higher glioma localization than that of single ligand-modified nanoparticles. After loading with docetaxel, a common chemotherapeutic, AnACNPs showed the most favorable antiglioma effect both in vitro and in vivo. In conclusion, a novel drug delivery system was developed for glioma dual targeting and glioma penetrating. The results demonstrated that the system effectively targeted gliomas and provided the most favorable antiglioma effect.

Carbon nanospheres (CNP) possess several unique properties that render CNP superior to traditional organic dyes and quantum dots in the biological application. However, the interaction of CNP with biological systems was far from well-known. In this study, a simple method using cocoon silk was used to synthesize photoluminescent CNP. The particle size of CNP was 100.6 nm with well dispersity. The excitation/emission wavelength was 340 nm and 442 nm. Cellular uptake demonstrated the uptake of CNP by A549 cells was a time-, concentration- and energy-dependent procedure. Endosome was involved in the uptake rather than mitochondria. Through several uptake inhibitors, it showed the uptake was energy-dependent and mainly mediated by clathrin-mediated endocytosis. In vivo, CNP were mainly distributed in heart and lung, while only a modest amount of CNP was distributed in spleen, liver and kidney. The distribution in tumor was relatively low, which made CNP a candidate for heart cell imaging. At as high as 2 mg/mL, CNP showed no obvious toxicity to cells. The hemolysis rate of CNP was also lower than 10%. These results suggested CNP was relatively safe in biological application.

Plasma protein binding with nanoparticles (NPs) occurs immediately upon their introduction into a physiological environment and is affected by the characteristics of NPs, including their composition, size, shape and surface properties. According to their specific functions, adsorbed proteins can be divided into opsonins and dysopsonins. Opsonins often induce the rapid blood clearance of NPs, while dysopsonins benefit prolonged blood circulation.This review discusses the influential factors that are involved in the interaction between NPs and plasma proteins. The influence of this interaction on distribution of NPs was reviewed followed by the function and influence of ligand modification.Protein adsorption is a key element that influences biological responses, such as endocytosis and biodistribution, and also contributes to the characteristics of NPs and the physiological environment. By contrast, the surface modification of ligands is a common and useful method to functionalize NPs to provide an engineered targeting effect. The protein adsorption of ligand-modified NPs is even more important and requires in-depth discussion. Differences between modified and unmodified NPs lead to varying degrees of opsonization, which greatly affects targeting and may result in opposing effects. Understanding these influences is necessary to improve targeting effects and reduce defects in protein adsorption, which are crucial for drug delivery.

Highly fluorescent carbon nanospheres with a quantum yield of 17.6% have been prepared by a one-step method with hydrothermal treatment of spider silk. Due to the high photostability, low toxicity and well blood compatibility, these carbon nanospheres could be used as an excellent probes for cancer cell imaging.