Effect of size on the thermal noise and acoustic response of viscous-driven microbeams.

A study is presented of the thermal-mechanical noise and response to sound of microphones that are designed to be driven by the viscous forces in air rather than by sound pressure. Virtually all existing microphone designs are intended to respond to sound pressure. The structures examined here consist of thin, micro-scale, cantilever beams. The viscous forces that drive the beams are proportional to the relative velocity between the beams and fluid medium. The beams' movement in response to sound is similar to that of the air in a plane acoustic wave. The thermal-mechanical noise of these beams is found to be a very weak function of their width and length; the size of the sensing structure does not appear to significantly affect the performance. This differs from the well-known importance of the size of a pressure-sensing microphone in determining the pressure-referred noise floor. Creating microphones that sense fluid motion rather than pressure could enable a significant reduction in the size of the sensing element. Calculated results are revealed to be in excellent agreement with the measured pressure-referred thermal noise.

Physical adsorption and oxidation of ultra-thin MoS2crystals: insights into surface engineering for 2D electronics and beyond.

The oxidation mechanism of atomically thin molybdenum disulfide (MoS2) plays a critical role in its nanoelectronics, optoelectronics, and catalytic applications, where devices often operate in an elevated thermal environment. In this study, we systematically investigate the oxidation of mono- and few-layer MoS2flakes in the air at temperatures ranging from 23 °C to 525 °C and relative humidities of 10%-60% by using atomic force microscopy (AFM), Raman spectroscopy and x-ray photoelectron spectroscopy. Our study reveals the formation of a uniform nanometer-thick physical adsorption layer on the surface of MoS2, which is attributed to the adsorption of ambient moisture. This physical adsorption layer acts as a thermal shield of the underlying MoS2lattice to enhance its thermal stability and can be effectively removed by an AFM tip scanning in contact mode or annealing at 400 °C. Our study shows that high-temperature thermal annealing and AFM tip-based cleaning result in chemical adsorption on sulfur vacancies in MoS2, leading to p-type doping. Our study highlights the importance of humidity control in ensuring reliable and optimal performance for MoS2-based electronic and electrochemical devices and provides crucial insights into the surface engineering of MoS2, which are relevant to the study of other two-dimensional transition metal dichalcogenide materials and their applications.

Selective CDK9 knockdown sensitizes TRAIL response by suppression of antiapoptotic factors and NF-kappaB pathway.

The aberrantly up-regulated CDK9 can be targeted for cancer therapy. The CDK inhibitor dinaciclib (Dina) has been found to drastically sensitizes cancer response to TRAIL-expressing extracellular vesicle (EV-T). However, the low selectivity of Dina has limited its application for cancer. We propose that CDK9-targeted siRNA (siCDK9) may be a good alternative to Dina. The siCDK9 molecules were encapsulated into EV-Ts to prepare a complexed nanodrug (siEV-T). It was shown to efficiently suppress CDK9 expression and overcome TRAIL resistance to induce strikingly augmented apoptosis in lung cancer both in vitro and in vivo, with a mechanism related to suppression of both anti-apoptotic factors and nuclear factor-kappa B pathway. Therefore, siEV-T potentially constitutes a novel, highly effective and safe therapy for cancers.

EV-T synergizes with AZD5582 to overcome TRAIL resistance through concomitant suppression of cFLIP, MCL-1, and IAPs in hepatocarcinoma.

Hepatocellular carcinoma (HCC) is an aggressive malignancy, and its effective treatment has been hampered by drug resistance. Extracellular vesicle (EV) delivery of TNF-related apoptosis-inducing ligand (TRAIL) (EV-T) was demonstrated to be superior to recombinant TRAIL (rTRAIL) for cancer treatment previously. And AZD5582, a potent antagonist of inhibitors of apoptosis proteins (IAPs) can potentiate apoptosis-based cancer therapies. However, the combination of EV-T and AZD5582 has never been examined for their possible apoptosis inducing synergism in cancers. In this study, we proposed and tested the combination of EV-T and AZD5582 as a potential novel therapy for effective treatment of HCC. Two HCC lines Huh7 and HepG2 that are both resistant to rTRAIL were examined. The results confirmed that AZD5582 and EV-T are synergistic for apoptosis induction in some cancer lines including Huh7 and HepG2 while sparing normal cells. More importantly, this study revealed that TRAIL sensitization by AZD5582 is mediated through the concomitant suppression of anti-apoptotic factors including cFLIP, MCL-1, and IAPs (XIAP, Survivin and cIAP-1). Particularly the downregulation of cFLIP and IAP's appeared to be essential and necessary for the synergism between AZD5582 and TRAIL. In vivo, we first time demonstrated that the combined therapy with low doses of AZD5582 and EV-Ts triggered drastically enhanced apoptosis leading to the complete eradication of Huh7 tumor development without any apparent adverse side effects examined. We thus have unraveled the important molecular mechanism underlying TRAIL sensitization by AZD5582, rationalizing the next development of a combination therapy with AZD5582 and EV-T for HCC treatment. KEY MESSAGES: It confirmed the TRAIL sensitization by AZD5582, a potent antagonist of IAPs in hepatocarcinoma. It revealed that the sensitization is via the concomitant suppression of antiapoptotic factors including cFLIP, MCL-1, and IAPs. The downregulation of cFLIP and IAPs like Survivin appeared to be essential and necessary for the synergism between AZD5582 and nanosomal TRAIL. In vivo the combined therapy with AZD5582 and nanosomal TRAIL led to complete eradication of hepatocarcinoma tumors. This study has rationalized the next development of a combination therapy with AZD5582 and nanosomal TRAIL for cancer treatment.

Extracellular vesicle-mediated co-delivery of TRAIL and dinaciclib for targeted therapy of resistant tumors.

Extracellular vesicle (EV) delivery of TNF-related apoptosis-inducing ligand (TRAIL) (EV-T) has been shown to be highly efficient for cancer treatment when combined with the potent cyclin-dependent kinase (CDK) inhibitor dinaciclib (SCH727965, Dina). However, only topical administration was previously tested for cancer treatment, leaving unknown the efficacy of systemic therapy by EV-T and Dina. In this study we hypothesize that the systemic application of EV-T and Dina can be performed through EV-mediated co-delivery of TRAIL and Dina. Dina was first post-loaded into EV-Ts by sonication to prepare EV-mediated co-delivery of TRAIL and Dina, designated Dina@EV-T. Then Dina@EV-Ts were shown to be stable, readily endocytosed into cancer cells, and highly effective at inducing intensive apoptosis in resistant cancer lines but not in normal cells. Moreover, systemically infused Dina@EV-Ts showed evident tumor tropism suggesting their good potential for tumour-targeted delivery of therapeutics. Importantly, the systemic therapy with Dina@EV-Ts showed the best efficacy in vivo when compared with other treatments. The augmented therapeutic efficacy appeared to be associated with the concomitant suppression of prosurvival CDK1 and anti-apoptotic proteins including CDK9, cFLIP, MCL-1, BCL-2 and Survivin by Dina@EV-T treatment. Additionally, there were no adverse side effects observed for the systemic Dina@EV-T therapy. In conclusion, our data suggest that the co-delivery of TRAIL and Dina by EVs potentially constitutes a novel tumour-targeted therapy, which is highly effective and safe for the treatment of refractory tumors.

Sensitizing TRAIL response via differential modulation of anti- and pro-apoptotic factors by AZD5582 combined with ER nanosomal TRAIL in neuroblastoma.

Neuroblastoma is a metastatic brain tumor particularly common in children. The cure rate is below 50% for patients of high-risk condition. Novel therapeutic agents and approaches are needed to improve the cure rate. Tumor necrosis factor-related and apoptosis-inducing ligand (TRAIL) is a promising proapoptotic factor that rapidly induces apoptosis preferentially in transformed and cancerous cells. Unfortunately, the common TRAIL resistance in cancers has hampered the clinical application of the ligand. Previously we prepared a novel TRAIL-armed ER derived nanosomal agent (ERN-T) that overcomes TRAIL resistance in some cancer lines when combined with a synthetic antagonist of inhibitors of apoptosis proteins (IAPs), AZD5582. However, how AZD5582 sensitizes cancer cells to ERN-T remains not well understood. In this study we continued to test the therapeutic efficacy of the combinatory therapy of ERN-T and AZD5582 on neuroblastoma, aiming to reveal the molecular mechanism underlying the synergism between AZD5582 and ERN-T. The obtained data revealed that ERN-Ts overcame TRAIL resistance and showed significant cytotoxicity on the resistant neuroblastoma line SH-SH5Y when combined with AZD5582 whilst sparing normal cells. The combination of low doses of ERN-Ts and AZD5582 induced intensive apoptosis in SH-SY5Y but not in normal skin fibroblasts (NSFs). Importantly we discovered that TRAIL sensitization in SH-SY5Y was associated with the concomitant downregulation of antiapoptotic factors cFLIP, MCL-1 and IAPs and upregulation of proapoptotic protein BAX and the death receptor 5 (DR5) by the cotreatment of ERN-T and AZD5582. In vivo study demonstrated that the combination of ERN-T and AZD5582 constituted a highly effective and safe therapy for subcutaneous SH-SY5Y xenograft neuroblastoma in nude mice. In conclusion, we identified that the concomitant regulation of both antiapoptotic and proapoptotic factors and DR5 is an essential molecular mechanism for overcoming TRAIL resistance in SH-SY5Y and the combination of ERN-T and AZD5582 potentially constitutes a novel therapeutic strategy, which is highly effective and safe for neuroblastoma.

Mitochondria-Targeted Triphenylphosphonium Conjugated C-3 Modified Betulin: Synthesis, Antitumor Properties and Mechanism of Action.

A series of mitochondria-targeted triphenylphosphonium conjugated C-3 modified betulin were synthesized and evaluated against tumor cells. As a result, a new derivative 13 i, the conjugate of 3-O-(3'-acetylphenylacetate)-betulin with triphenylphosphonium, was identified as the one with the best anti-tumor effect. Conjugate 13 i significantly inhibited HCT116 cells with IC50 at 0.66 µM. While betulin, C-3 modified betulin, and the triphenylphosphonium moiety showed no inhibition of HCT116 cell proliferation at 20 µM. More importantly, 13 i exhibited a more cytotoxic effect against the tumor cell HCT116 than normal cell NCM460. Mode of action studies demonstrated that 13 i induced the G2/M phase cell cycle arrest and apoptosis in HCT116 cells through the mitochondrial pathway. Structure-activity relationship analysis revealed that integration of triphenylphosphonium moiety into the C-28 of betulin can greatly improve cytotoxicity. Appropriate modification on C-3 of the conjugate would improve the selectivity.

Antler stem cells and their potential in wound healing and bone regeneration.

Compared to other vertebrates, the regenerative capacity of appendages in mammals is very limited. Deer antlers are an exception and can fully regenerate annually in postnatal mammals. This process is initiated by the antler stem cells (AnSCs). AnSCs can be divided into three types: (1) Antlerogenic periosteum cells (for initial pedicle and first antler formation); (2) Pedicle periosteum cells (for annual antler regeneration); and (3) Reserve mesenchyme cells (RMCs) (for rapid antler growth). Previous studies have demonstrated that AnSCs express both classic mesenchymal stem cells (MSCs) and embryonic stem cells (ESCs), and are able to differentiate into multiple cell types in vitro. Thus, AnSCs were defined as MSCs, but with partial ESC attributes. Near-perfect generative wound healing can naturally occur in deer, and wound healing can be achieved by the direct injection of AnSCs or topical application of conditioned medium of AnSCs in rats. In addition, in rabbits, the use of both implants with AnSCs and cell-free preparations derived from AnSCs can stimulate osteogenesis and repair defects of bone. A more comprehensive understanding of AnSCs will lay the foundation for developing an effective clinical therapy for wound healing and bone repair.

TRAIL-Armed ER Nanosomes Induce Drastically Enhanced Apoptosis in Resistant Tumor in Combination with the Antagonist of IAPs (AZD5582).

Although mesenchymal stem cells (MSCs) can be engineered to deliver the TNF-related apoptosis-inducing ligand (TRAIL) as an effective anticancer therapy, the clinical application is hampered by the costly manufacturing of therapeutic MSCs. Therefore, it is needed to find an alternative cell-free therapy. In this study, TRAIL-armed endoplasmic reticulum (ER)-derived nanosomes (ERN-T) are successfully prepared with an average size of 70.6 nm in diameter from TRAIL transduced MSCs. It is demonstrated that the ERN-T is significantly more efficient for cancer cell killing than the soluble recombinant TRAIL (rTRAIL). AZD5582 is an antagonist of the inhibitors of apoptosis proteins (IAPs), and its combination with ERN-T induces strikingly enhanced apoptosis in cancerous but not normal cells. AZD5582 sensitizes resistant cancer cells to TRAIL through concomitant downregulation of IAP members like XIAP and the Bcl2 family member Mcl-1. Intravenously infused ERN-Ts accumulate in tumors for over 48 h indicating good tumor tropism and retention. The combination of ERN-T and AZD5582 drastically promotes therapeutic efficacy comparing with the cotreatment by rTRAIL and AZD5582 in a subcutaneous MDA-MB-231 xenograft tumor model. The data thus demonstrate that ERN-T can be a novel cell-free alternative to TRAIL-expressing MSC-based anticancer therapy and its efficacy can be drastically enhanced through combination with AZD5582.

Extracellular Vesicle Delivery of TRAIL Eradicates Resistant Tumor Growth in Combination with CDK Inhibition by Dinaciclib.

Tumour necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) is a promising anti-cancer agent that rapidly induces apoptosis in cancer cells. Unfortunately, the clinical application of recombinant TRAIL (rTRAIL) has been hampered by its common cancer resistance. Naturally TRAIL is delivered as a membrane-bound form by extracellular vesicles (EV-T) and is highly efficient for apoptosis induction. SCH727965 (dinaciclib), a potent cyclin-dependent kinase (CDK) inhibitor, was shown to synergize with other drugs to get better efficacy. However, it has never been investigated if dinaciclib coordinates with EV-T to enhance therapeutic results. This study explores the potential of combination therapy with EV-T and dinaciclib for cancer treatment. EV-T was successfully derived from human TRAIL transduced cells and shown to partially overcome resistance of A549 cells. Dinaciclib was shown to drastically enhance EV-T killing effects on cancer lines that express good levels of death receptor (DR) 5, which are associated with suppression of CDK1, CDK9 and anti-apoptotic proteins. Combination therapy with low doses of EV-T and dinaciclib induced strikingly enhanced apoptosis and led to complete regression in A549 tumors without any adverse side effects observed in a subcutaneous xenograft model. Tumor infiltration of mass NK cells and macrophages was also observed. These observations thus indicate that the combination of EV-T with dinaciclib is a potential novel therapy for highly effective and safe cancer treatment.

Direct nanomechanical measurements of boron nitride nanotube-ceramic interfaces.

Boron nitride nanotubes (BNNTs) are a unique class of light and strong tubular nanostructure and are highly promising as reinforcing additives in ceramic materials. However, the mechanical strength of BNNT-ceramic interfaces remains largely unexplored. Here we report the first direct measurement of the interfacial strength by pulling out individual BNNTs from silica (silicon dioxide) matrices using in situ electron microscopy techniques. Our nanomechanical measurements show that the average interfacial shear stress reaches about 34.7 MPa, while density functional theory calculations reveal strong bonded interactions between BN and silica lattices with a binding energy of -6.98 eV nm-2. Despite this strong BNNT-silica binding, nanotube pull-out remains the dominant failure mode without noticeable silica matrix residues on the pulled-out tube surface. The fracture toughness of BNNT-silica ceramic matrix nanocomposite is evaluated based on the measured interfacial strength property, and substantial fracture toughness enhancements are demonstrated at small filler concentrations.

Author Correction: Quantitative Characterization of Structural and Mechanical Properties of Boron Nitride Nanotubes in High Temperature Environments.

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Quantitative Characterization of Structural and Mechanical Properties of Boron Nitride Nanotubes in High Temperature Environments.

The structural stability and mechanical integrity of boron nitride nanotubes (BNNTs) in high temperature environments are of importance in pursuit of their applications that are involved with extreme thermal processing and/or working conditions, but remain not well understood. In this paper, we perform an extensive study of the impacts of high temperature exposure on the structural and mechanical properties of BNNTs with a full structural size spectrum from nano- to micro- to macro-scale by using a variety of in situ and ex situ material characterization techniques. Atomic force microscopy (AFM) and high resolution transmission electron microscopy measurements reveal that the structures of individual BNNTs can survive at up to 850 °C in air and capture the signs of their structural degradation at 900 °C or above. In situ Raman spectroscopy measurements reveal that the BN bonds in BNNT micro-fibrils undergo substantial softening at elevated temperatures of up to 900 °C. The AFM-based nanomechanical compression measurements demonstrate that the mechanical integrity of individual BNNTs remain intact after being thermally baked at up to 850 °C in air. The studies reveal that BNNTs are structurally and mechanically stable materials in high temperature environments, which enables their usages in high temperature applications.

Synergistic anti-tumor therapy by a comb-like multifunctional antibody nanoarray with exceptionally potent activity.

Simultaneously blocking multiple mediators offers new hope for the treatment of complex diseases. However, the curative potential of current combination therapy by chronological administration of separate monoclonal antibodies (mAbs) or multi-specific mAbs is still moderate due to inconvenient manipulation, low cooperative effectors, poor pharmacokinetics and insufficient tumor accumulation. Here, we describe a facile strategy that arms distinct mAbs with cooperative effectors onto a long chain to form a multicomponent comb-like nano mAb. Unlike dissociative parental mAbs, the multifunctional mAb nanoarray (PL-RB) constructed from type I/II anti-CD20 mAbs shows good pharmacokinetics. This PL-RB simultaneously targets distinct epitopes on a single antigen (Ag) and neighboring Ags on different lymphocytes. This unique intra- and intercellular Ag cross-linking endows the multifunctional mAb nanoarray with potent apoptosis activity. The exceptional apoptosis, complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) that are synchronously evoked by the nano PL-RB are further synergistically promoted via enhanced permeability and retention (EPR), which resulted in high intratumor accumulation and excellent anti-lymphoma efficiency.

Suppression of Rituximab-resistant B-cell lymphoma with a novel multi-component anti-CD20 mAb nanocluster.

Although the anti-CD20 antibody Rituximab has revolutionized the treatment of Non-Hodgkin Lymphoma (NHL), resistance to treatment still existed. Thus, strategies for suppressing Rituximab-resistant NHLs are urgently needed. Here, an anti-CD20 nanocluster (ACNC) is successfully constructed from its type I and type II mAb (Rituximab and 11B8). These distinct anti-CD20 mAbs are mass grafted to a short chain polymer (polyethylenimine). Compared with parental Rituximab and 11B8, the ACNC had a reduced "off-rate". Importantly, ACNC efficiently inhibited Rituximab-resistant lymphomas in both disseminated and localized human NHL xenograft models. Further results revealed that ACNC is significantly potent in inducing caspase-dependent apoptosis and lysosome-mediated programmed cell death (PCD). This may help explain why ACNC is effective in suppressing rituximab-resistant lymphoma while Rituximab and 11B8 are not. Additionally, ACNC experienced low clearance from peripheral blood and high intratumor accumulation. This improved pharmacokinetics is attributed to the antibody-antigen reaction (active targeting) and enhanced permeability and retention (ERP) effect (passive targeting). This study suggested that ACNC might be a promising therapeutic agent for treatment of rituximab-resistant lymphomas.

Construction and characterization of an anti-CD20 mAb nanocomb with exceptionally excellent lymphoma-suppressing activity.

The CD20-directed monoclonal antibody rituximab (RTX) established a new era in the treatment of non-Hodgkin lymphoma (NHL); however, suboptimal response and/or resistance to RTX still limit its clinical merits. Although four effector mechanisms are validated to participate in CD20-based immunotherapy, including complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, caspase-dependent apoptosis, and lysosome-mediated programmed cell death (PCD), they could hardly be synchronously activated by any anti-CD20 mAb or mAb derivative until now. Herein, a novel mAb nanocomb (polyethylenimine polymer-RTX-tositumomab [PPRT nanocomb]) was firstly constructed through mass arming two different anti-CD20 mAbs (RTX and tositumomab) to one polymer by nanotechnology. Comparing with free mAbs, PPRT nanocomb possesses a comparable binding ability and reduced "off-rate" to surface CD20 of NHL cells. When treated by PPRT nanocomb, the caspase-dependent apoptosis was remarkably enhanced except for concurrently eliciting complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and lysosome-mediated PCD. Besides, "cross-cell link"-assisted homotypic adhesion by PPRT nanocomb further enhanced the susceptibility to PCD of lymphoma cells. Pharmacokinetic assays revealed that PPRT nanocomb experienced a relatively reduced clearance from peripheral blood compared with free antibodies. With the cooperation of all the abovementioned superiorities, PPRT nanocomb exhibits exceptionally excellent in vivo antitumor activities in both disseminated and localized human NHL xenotransplant models.

A redox-sensitive micelle-like nanoparticle self-assembled from amphiphilic adriamycin-human serum albumin conjugates for tumor targeted therapy.

The application of chemotherapeutic drug adriamycin (ADR) in cancer therapy is limited by its side effects like high toxicity and insolubility. Nanomedicine offers new hope for overcoming the shortcomings. But how to increase in vivo stability and to control intracellular drug release is a key issue for nano-based formulations. Herein, the hydrophobic ADR was successfully linked to the biocompatible human serum albumin (HSA) by disulfide bond 3-(2-pyridyldithio) propionyl hydrazide (PDPH), resulting in amphiphilic HSA-ADR. The novel ADR-HSA micellar NPs which were thus assembled exhibited a well-defined stable core shell structure with glutathione (GSH) sensitive linkers. The stable PDPH linkers at extracellular level were broken by GSH at intracellular level with a controlled ADR release profile. The in vitro cytotoxicity against gastric cancer cells (NCI-N87) was obviously enhanced by such redox-sensitive ADR-HSA NPs. Additionally, as observed by IVIS Lumina II Imaging System (Xenogen), the intratumor accumulation of ADR-HSA NPs was much higher than that of HSA/ADR NPs due to its high stability. Consequently, the in vivo tumor inhibition was significantly promoted after intravenous administration to the Balb/c nude mice bearing gastric tumors. These in vitro/vivo results indicated that disulfide-bond-containing ADR-HSA NPs were an effective nanodrug delivery system for cancer therapy.

WITHDRAWN: Effective suppression of Rituximab-resistant B-cell lymphoma by a comb-like anti-CD20 mAb nanocluster.

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Migration mechanism of mesenchymal stem cells studied by QD/NSOM.

The migration of mesenchymal stem cells (MSCs) plays a key role in tumor-targeted delivery vehicles and tumor-related stroma formation. However, there so far has been no report on the distribution of cell surface molecules during the VEGF-induced migration of MSCs. Here, we have utilized near-field scanning optical microscopy (NSOM) combined with fluorescent quantum dot (QD)-based nano-technology to capture the functional relationship between CD44 and CD29 adhesion molecules on MSCs and the effect of their spatial rearrangements. Before VEGF-induced migration of MSCs, both CD44 and CD29 formed 200-220 nm nano-domains respectively, with little co-localization between the two types of domains. Surprisingly, the size of the CD44 nano-domain rapidly increased in size to 295 nm and apparently larger aggregates were formed following MSC treatment with VEGF for 10 min, while the area of co-localization increased to 0.327 µm2. Compared with CD44, CD29 was activated obviously later, for the fact that CD29 aggregation didn't appear until 30 min after VEGF treatment. Consistently, its co-localization area increased to 0.917 µm2. The CD44 and CD29 nano-domains further aggregated into larger nano-domains or even formed micro-domains on the membrane of activated MSCs. The aggregation and co-localization of these molecules promoted FAK formation and cytoskeleton rearrangement. All of the above changes induced by VEGF contributed to MSC migration. Taken together, our data of NSOM-based dual color fluorescent imaging demonstrated for the first time that CD44, together with CD29, involved in VEGF-induced migration of MSCs through the interaction between CD44 and its co-receptor of VEGFR-2.

Nano polymeric carrier fabrication technologies for advanced antitumor therapy.

Comparing with the traditional therapeutic methods, newly developed cancer therapy based on the nanoparticulates attracted extensively interest due to its unique advantages. However, there are still some drawbacks such as the unfavorable in vivo performance for nanomedicine and undesirable tumor escape from the immunotherapy. While as we know that the in vivo performance strongly depended on the nanocarrier structural properties, thus, the big gap between in vitro and in vivo can be overcome by nanocarrier's structural tailoring by fine chemical design and microstructural tuning. In addition, this fine nanocarrier's engineering can also provide practical solution to solve the problems in traditional cancer immunotherapy. In this paper, we review the latest development in nanomedicine, cancer therapy, and nanoimmunotherapy. We then give an explanation why fine nanocanrrie's engineering with special focus on the unique pathology of tumor microenvironments and properties of immunocells can obviously promote the in vivo performance and improve the therapeutic index of nanoimmunotherapy.