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T cells play a determining role in the immunomodulation and prognostic evaluation of cancer treatments relying on immune activation. While specific biomarkers determine the population and distribution of T cells in tumours, the in situ activity of T cells is less studied. Here we designed T-cell-targeting fusogenic liposomes to regulate and quantify the activity of T cells by exploiting their surface redox status as a chemical target. The T-cell-targeting fusogenic liposomes equipped with 2,2,6,6-tetramethylpiperidine (TEMP) groups neutralize reactive oxygen species protecting T cells from oxidation-induced loss of activity. Meanwhile, the production of paramagnetic 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) radicals allows magnetic resonance imaging quantification of the T cell activity. In multiple mouse models, the T-cell-targeting fusogenic liposomes led to efficient tumour inhibition and to early prediction of radiotherapy outcomes. This study uses a chemical targeting strategy to measure the in situ activity of T cells for cancer theranostics and may provide further understanding on engineering T cells for cancer treatment.

Metastasis of breast cancer is key to poor prognosis and high mortality. However, the excess reactive oxygen species (ROS) and inflammatory response induced by photothermal therapy (PTT) further aggravate tumor metastasis. Meanwhile, the hypoxic tumor microenvironment promotes tumor cells to metastasize to distant organs. Herein, the intrinsic limitations of PTT for metastatic tumor have been addressed by fabricating polyethylene glycol modified iridium tungstate (IrWO

Naturally inspired proteins are investigated for the development of bioglues that combine adhesion performance and biocompatibility for biomedical applications. However, engineering such adhesives by rational design of the proteins at the molecular level is rarely reported. Herein, it is shown that a new generation of protein-based glues is generated by supramolecular assembly through de novo designed structural proteins in which arginine triggers robust liquid-liquid phase separation. The encoded arginine moieties significantly strengthen multiple molecular interactions in the complex, leading to ultrastrong adhesion on various surfaces, outperforming many chemically reacted and biomimetic glues. Such adhesive materials enable quick visceral hemostasis in 10 s and outstanding tissue regeneration due to their robust adhesion, good biocompatibility, and superior antibacterial capacity. Remarkably, their minimum inhibitory concentrations are orders of magnitude lower than clinical antibiotics. These advances offer insights into molecular engineering of de novo designed protein glues and outline a general strategy to fabricate mechanically strong protein-based materials for surgical applications.

Diffuse intrinsic pontine glioma (DIPG) is a rare and fatal pediatric brain tumor. Mutation of p53-induced protein phosphatase 1 (PPM1D) in DIPG cells promotes tumor cell proliferation, and inhibition of PPM1D expression in DIPG cells with PPM1D mutation effectively reduces the proliferation activity of tumor cells. Panobinostat effectively kills DIPG tumor cells, but its systemic toxicity and low blood-brain barrier (BBB) permeability limits its application. In this paper, a nano drug delivery system based on functionalized macrophage exosomes with panobinostat and PPM1D-siRNA for targeted therapy of DIPG with PPM1D mutation is prepared. The nano drug delivery system has higher drug delivery efficiency and better therapeutic effect than free drugs. In vivo and in vitro experimental results show that the nano drug delivery system can deliver panobinostat and siRNA across the BBB and achieve a targeted killing effect of DIPG tumor cells, resulting in the prolonged survival of orthotopic DIPG mice. This study provides new ideas for the delivery of small molecule drugs and gene drugs for DIPG therapy.

Ionic liquid (IL)-loaded or metal ions-enriched nanoparticles have been witnessed to assist microwave ablation (MWA) and heighten heat utilization for tumor treatment, which, however, inevitably brings about cell dys-homeostasis and severely endangers normal cells or tissues. In this report, a nonionic MWA sensitizer that encapsulates ethyl formate (EF) and doxorubicin (DOX) in liposomes (EF-DOX-Lips) was constructed to reinforce MWA and combined therapy against incomplete MWA-induced tumor recurrence. EF in EF-DOX-Lips as the nonionic liquid can perform like IL to accelerate energy transformation from electromagnetic energy to heat for strengthening MWA. More significantly, EF metabolite, that is, ethanol, also enables chemical ablation, which further enhances MWA. As well, the EF gasification-enhanced lipid rupture and cavitation can promote DOX delivery into a liver tumor for magnifying MWAamp; chemotherapy combined therapy. By virtue of these contributions, this nonionic MWA nanosensitizer exerts robust antitumor effects to inhibit tumor proliferation and angiogenesis for repressing tumor growth and recurrence or metastasis via downregulating theiEpha2/igene and unconventional PI3K/Aktamp; MAPK signal pathways that the incomplete MWA activated, which provides an avenue to elevate an MWA-based antitumor outcome.

Pharmaceutical evaluations of nanomedicines are of great significance for their further launch into industry and clinic. Near-infrared (NIR) fluorescence imaging plays essential roles in preclinical drug development by providing important insights into the biodistributions of drugs in vivo with deep tissue penetration and high spatiotemporal resolution. However, NIR-II fluorescence imaging has rarely been exploited for in vivo real-time pharmaceutical evaluations of nanomedicine. Herein, we developed a highly emissive NIR-II luminophore to establish a versatile nanoplatform to noninvasively monitor the in vivo metabolism of nanomedicines bound various polyethylene glycol (PEG) ligands in a real-time manner. An alternative D-A-D conjugated oligomer (DTTB) was synthesized to achieve NIR-II emission peaked at ∼1050 nm with high fluorescence QYs of 13.4% and a large absorption coefficient. By anchoring with the DTTB molecule, intrinsically fluorescent micelles were fabricated and bound with PEG ligands at various chain lengths. In vivo NIR-II fluorescence and photoacoustic imaging results revealed that an appropriate PEG chain length could effectively contribute to the longer blood circulation and better tumor targeting. In vivo therapeutic experiments also confirmed the optimized nanomedicines have efficient photothermal elimination of tumors and good biosafety. This work offered an alternative highly fluorescent NIR-II material and demonstrated a promising approach for real-time pharmaceutical evaluation of nanomedicine in vivo.

Small interfering RNA (siRNA) shows excellent pharmaceutical prospects in treating diverse life-threatening diseases. Photodynamic therapy (PDT) is a clinically employed noninvasive treatment method that can trigger selective damage toward targeted tissue and cells. However, insufficient delivery of siRNA and photosensitizer to cancer cells remarkably hindered the application of siRNA and PDT in the treatment of cancer. In this study, a unique reactive oxygen species (ROS)-activatable polyplex, which consists of the PEGylated cationic polymer, ROS-cleavable linker, photosensitizer Ce6, and RRM2-against siRNA, termed PPTC/siRNA, was engineered. Upon irradiation of near-infrared (NIR) light, the polyplex efficiently generated ROS, which triggered degradation of the ROS-sensitive linker, disassembling the complex, destabilization of the cell membrane, and significantly accelerated cellular entry and endosomal escape of siRNA. Besides achieving effective siRNA internalization and gene silence in cancer cells in vitro, PPTC/siRNA synergistically inhibited tumor growth in both cell line-derived xenograft and patient-derived xenograft hepatocellular carcinoma murine models by repressing the RRM2 expression (reducing cell proliferation) and triggering photodynamic killing (enhancing cell apoptosis). The proposed polyplex also showed ideal safety profiles both in cell line and in animal. It provides a novel strategy for NIR-triggered RNAi and PDT combinational cancer treatment.

We developed a biodegradable photothermal therapeutic (PTT) agent, π-conjugated oligomer nanoparticles (F8-PEG NPs), for highly efficient cancer theranostics. By exploiting an oligomer with excellent near-infrared (NIR) absorption, the nanoparticles show a high photothermal conversion efficiency (PCE) up to 82%, surpassing those of reported inorganic and organic PTT agents. In addition, the oligomer nanoparticles show excellent photostability and good biodegradability. The F8-PEG NPs are also demonstrated to have excellent biosafety and PTT efficacy both in vitro and in vivo. This contribution not only proposes a promising oligomer-based PTT agent but also provides insight into developing highly efficient nanomaterials for cancer theranostics.

Reactive oxygen species (ROS) are crucial molecules in cancer therapy. Unfortunately, the therapeutic efficiency of ROS is unsatisfactory in clinic, primarily due to their rigorous production conditions. By taking advantage of the intrinsic acidity and overproduction of H2O2 in the tumor environment, we have reported an ROS nanoreactor based on core-shell-structured iron carbide (Fe5C2@Fe3O4) nanoparticles (NPs) through the catalysis of the Fenton reaction. These NPs are able to release ferrous ions in acidic environments to disproportionate H2O2 into •OH radicals, which effectively inhibits the proliferation of tumor cells both in vitro and in vivo. The high magnetization of Fe5C2@Fe3O4 NPs is favorable for both magnetic targeting and T2-weighted magnetic resonance imaging (MRI). Ionization of these NPs simultaneously decreases the T2 signal and enhances the T1 signal in MRI, and this T2/T1 switching process provides the visualization of ferrous ions release and ROS generation for the supervision of tumor curing. These Fe5C2@Fe3O4 NPs show great potential in endogenous environment-excited cancer therapy with high efficiency and tumor specificity and can be guided further by MRI.

Gastrointestinal diseases affect many people in the world and significantly impair life quality and burden the healthcare system. The functional parameters of the gastrointestinal tract such as motility and pH can effectively reflect the changes of gastrointestinal activity in physiological and pathological conditions. Thus, a noninvasive method for real-time and quantitative measurement of gastrointestinal functional parameters in vivo is highly desired. At present, there are many strategies widely used for the diagnosis of gastrointestinal diseases in clinic, including X-ray barium meal examination, ultrasound imaging, radionuclide examination, endoscopy, etc. However, these methods are limited in determining the gastrointestinal status and cannot provide comprehensive quantitative information. Photoacoustic imaging (PAI) is a rapid noninvasive real-time imaging technique in which multiple types of functional and quantitative information can be simultaneously obtained. Unfortunately, very few ratiometric PAI contrast agents have been reported for quantification of gastrointestinal functional parameters in vivo. In this work, a broad, pH-responsive ratiometric sensor based on polyaniline and Au triangular nanoplates was developed. Utilizing the sensor as a contrast agent, PAI served as an all-in-one technique, accurately measuring the gastrointestinal functional parameters in a single test. Notably, this sensor was examined to be ultrasensitive with pH responses as fast as 0.6 s and durability as long as 24 h, and was repeatable and reversible for longitudinal monitoring. The quantitative results demonstrated a significant disorder in motility and decrease in pH for gastric and duodenal ulcers. Collectively, the combination of PAI and this broad pH-responsive sensor might be a promising candidate for quantitative diagnosis of gastrointestinal diseases.

Various nanoparticles have been employed for gene delivery. Revealing the endocytosis or phagocytosis behaviors of the gene delivery system is critical for designing sophisticated gene therapies. Herein, a kind of water-soluble PEI capped AgInS/ZnS (ZAIS@PEI) quantum dot was synthesized as a self-indicating gene vector in the presence of branched polyethylenimine (PEI) and mercaptopropionic acid (MPA). The as-prepared ZAIS@PEI QDs could efficiently condense plasmid DNA into nanocomplexes with strong fluorescence, which can reveal their positions during gene transfection. Our results confirmed that ZAIS@PEI could mediate plasmid DNA delivery into HeLa cells with the high transfection efficiency of 40% and low cytotoxicity, meanwhile allowing the real-time monitoring of gene transfection. The obtained ZAIS@PEI QDs were verified as versatile self-tracking gene vectors, which integrated gene delivery with bioimaging functions without external labeling.

Seeking profitable therapies for triple-negative breast cancer (TNBC) has attracted intense research interest. However, an efficient cure for TNBC remains an unresolved challenge in oncology. Herein, for the first time, we describe the use of polymeric nanoparticles loaded with NVP-BEZ235 and Chlorin-e6, denoted as NVP/Ce6@NPs, to overcome the adaptive treatment tolerance of TNBC by taking advantage of the synergistic effect between biochemical and photodynamic therapies. Upon laser irradiation, the NVP/Ce6@NPs generated reactive oxygen species (ROS) and efficiently induced the apoptosis of tumor cells through DNA damage. Furthermore, the released NVP-BEZ235 could prevent Chk1 phosphorylation-induced DNA damage repair, thus enhancing the sensitivity of tumor cells to ROS. Animal studies on mice bearing an MDA- MB-231 tumor validated that the NVP/Ce6@NPs had a greater therapeutic efficacy compared to that of monotherapies, with an inhibition ratio of 89.3%. Western blotting and cell viability analyses confirmed the inhibition of both MDA-MB-231 cell proliferation and Chk1 phosphorylation by NVP/Ce6@NPs. These findings provide a rational understanding of the synergistic effect of the biochemical/photodynamic therapy and pave the way for the development of efficient therapeutic approaches to fight against TNBC.

Nanotechnology has been considered as a promising strategy for diagnosis and treatment of various diseases. However, the stability and circulation times of the conventional nano-carriers, such as liposomes and micelles, are still unsatisfied. Perfluorocarbons (PFCs) are biologic inert synthetic materials, which are highly hydrophobic and have a tendency to self-aggregation. Additionally, PFCs themselves can act as 19F magnetic resonance imaging agents and oxygen carriers. Thus, the construction of the fluorinated carriers will not only improve the stability of the carriers, but also endow them with additional functions. Here we review the recent advances of PFC-based nanosystems for diagnosis and treatment of diseases.

Viruses have evolved to be outstandingly efficient at gene delivery, but their use as vectors is limited by safety risks. Inspired by the structure of viruses, we constructed a virus-mimicking vector (denoted as TR4@siRNA@Tf NCs) with virus-like architecture and infection properties. Composed of a hydrophilic peptide, an aggregation-induced emission (AIE) luminogen, and a lipophilic tail, TR4 imitates the viral capsid and endows the vector with AIE properties as well as efficient siRNA compaction. The outer glycoprotein transferrin (Tf) mimics the viral envelope protein and endows the vector with reduced cytotoxicity as well as enhanced targeting capability. Because of the strong interaction between Tf and transferrin receptors on the cell surface, the Tf coating can accelerate the intracellular release of siRNA into the cytosol. Tf and TR4 are eventually cycled back to the cell membrane. Our results confirmed that the constructed siRNA@TR4@Tf NCs show a high siRNA silencing efficiency of 85% with significantly reduced cytotoxicity. These NCs have comparable transfection ability to natural viruses while avoiding the toxicity issues associated with typical nonviral vectors. Therefore, this proposed virus-like siRNA vector, which integrates the advantages of both viral and nonviral vectors, should find many potential applications in gene therapy.

The proliferation of vascular smooth muscle cells (VSMCs) is one of the key events during the progress of atherosclerosis. The activated liver X receptor (LXR) signalling pathway is demonstrated to inhibit platelet-derived growth factor BB (PDGF-BB)-induced VSMC proliferation. Notably, following PDGF-BB stimulation, the expression of intercellular adhesion molecule-1 (ICAM-1) by VSMCs increases significantly. In this study, anti-ICAM-1 antibody-conjugated liposomes were fabricated for targeted delivery of a water-insoluble LXR agonist (T0901317) to inhibit VSMC proliferation. The liposomes were prepared by filming-rehydration method with uniform size distribution and considerable drug entrapment efficiency. The targeting effect of the anti-ICAM-T0901317 liposomes was evaluated by confocal laser scanning microscope (CLSM) and flow cytometry. Anti-ICAM-T0901317 liposomes showed significantly higher inhibition effect of VSMC proliferation than free T0901317 by CCk8 proliferation assays and BrdU staining. Western blot assay further confirmed that anti-ICAM-T0901317 liposomes inhibited retinoblastoma (Rb) phosphorylation and MCM6 expression. In conclusion, this study identified anti-ICAM-T0901317 liposomes as a promising nanotherapeutic approach to overcome VSMC proliferation during atherosclerosis progression. Electronic supplementary material The online version of this article (doi:10.1186/s11671-017-2097-6) contains supplementary material, which is available to authorized users.

At present, enzyme-linked immunosorbent assay (ELISA) is considered to be the most appropriate approach in clinical biomarker detection, with good specificity, low cost, and straightforward readout. However, unsatisfactory sensitivity severely hampers its wide application in clinical diagnosis. Herein, we designed a new kind of enhanced fluorescence enzyme-linked immunosorbent assay (FELISA) based on the human alpha-thrombin (HAT) triggering fluorescence “turn-on” signals. In this system, detection antibodies (Ab2) and HAT were labeled on the gold nanoparticles (AuNPs) to form the detection probes, and a bisamide derivative of Rhodamine110 with fluorescence quenched served as the substrate of HAT. After the sandwich immunoreaction, HAT on the sandwich structure could catalyze the cleavage of the fluorescence-quenched substrate, leading to a strong fluorescence signal for sensing ultralow levels of alpha fetoprotein (AFP) and hepatitis B virus surface antigen (HBsAg). Under the optimized reaction condition...

Currently, protein/peptide-based biomimetic mineralization has been demonstrated to be an efficient and promising strategy for synthesis of inorganic/metal nanoparticles (NPs) for bioapplications. This strategy is found to be bio-inspired, straightforward, and environmentally benign. It can produce inorganic/metal NPs with good stability, excellent biocompatibility, high water solubility, and rich surface functional groups for further bioconjunction. In this review, we provide a summary of the previously reported proteins/peptides as biotemplates involved in biomimetic mineralization synthesis, and categorize the obtained inorganic NPs ranging from metal nanoclusters (MNCs), quantum dots (QDs), gadolinium derivatives, and metal sulfide nanoparticles (MSNPs) with an emphasis on the recent progress in their use in biomedical applications, including bio-sensing, ion detection, bio-labeling, in vivo imaging and therapy. In the end, the challenges and future outlook in this emerging area are also discussed.

Nitric oxide (NO) has been well identified as a specific free radical molecule possessing wide-ranging therapeutic effects. Targeted delivery and controlled release of NO are highly desired to realize precision gas therapy, but are still challenging owing to the non-targetability and uncontrollability of NO itself. Herein, we propose a new concept of MRI-guided and ultrasound-triggered gas release for precision gas therapy. Based on this concept, we develop a novel ultrasound-responsive BNN-type NO-releasing molecule (NORM) and an advanced rattle-type nano-carrier of superparamagnetic iron oxide-encapsulated mesoporous silica nanoparticles (SPION@hMSN), and use them to construct a new intelligent nanomedicine (BNN6-SPION@hMSN) for the first time. The BNN6-SPION@hMSN nanomedicine exhibits excellent passive tumor-targeting capability, high MRI-guided tumor localization performance and a unique ultrasound-triggered NO release profile. The tumor-targeted, MRI-guided and ultrasound-triggered release profiles of the developed nanomedicine enable the tumor site-specific controlled release of NO in favor of high-efficacy and safe NO gas therapy of tumor.

Carrier-free nanodrugs formulated from the supramolecular self-assembly of pure drug molecules have emerged as an innovative and promising strategy for tumor therapy. We report herein a new and simple method to directly assemble a small hydrophobic anticancer drug, 10-hydroxycamptothecin (HCPT), with a photosensitizer chlorin e6 (Ce6) to form stable, discrete nanorods (NRs), which not only circumvent the extreme hydrophobicity of HCPT but also incorporate two different modalities into one delivery system for combination therapy. Different ratios of HCPT to Ce6 were evaluated to afford the optimal nanoformulation. The as-prepared HCPT/Ce6 NRs were fully characterized, indicating a relatively uniform size of about 360 nm in length and 135 nm in width, and a surface charge of about -33 mV. Efficient internalization of the NRs by cancer cells was observed by using a confocal microscope and the generation of singlet oxygen species arising from the NRs under 655 nm laser irradiation was detected by DCFH-DA. As a result, very potent in vitro efficacy against several kinds of cancer cell lines was achieved through chemo-photodynamic dual therapy. The in vivo tumor suppression effect of HCPT/Ce6 NRs was verified on a subcutaneous xenograft mouse model, achieving almost complete inhibition of the tumor growth, which may benefit from the superiority of nanomedicine and combination therapy. The rationale of this facile and green strategy for carrier-free nanodrug formulation via the self-assembly approach might provide new opportunities for the development of combinatorial therapeutics for tumors.

The combination of antiangiogenesis with chemotherapy has become a promising multi-modal combinational therapy for solid tumor. However, hypoxia-mediated resistance and the subsequent treatment failure associated with antiangiogenesis therapy have limited the maximization of this promising approach. It remains a major challenge to balance the effect of angiogenesis and the accumulation of the cytotoxic drug within the tumor microenvironment. In this study, we report a nanotechnology based drug delivery solution that would improve both the antiangiogenic activity and cytotoxic efficacy of the loaded drugs. We designed core-shell 'lipid nanocells' drug delivery systems (denoted as DTX/ITZ-LNCs), which entrapped the antiangiogenic drug itraconazole (ITZ) in the outside liposomal shell and encapsulated anticancer drug docetaxel (DTX) in the inner hydrophobic PLGA core. In vitro evaluations showed that the dual drug loaded DTX/ITZ-LNCs retained the cytotoxic efficacy of the DTX against both the sensitive and multidrug resistant breast cancer cell line MCF-7. DTX/ITZ-LNCs also effectively inhibited the vascular endothelial growth factor (VEGF) induced migratory and invasive actions of HUVECs and neovascularization of subcutaneously implanted matrigel plugs. The tumor growth of MCF-7 tumor xenograft model was effectively inhibited by the systemic administration of the DTX/ITZ-LNCs. Taken together, these results showed that the DTX/ITZ-LNCs provided a drug delivery platform that can optimize the combinatory effects of the antiangiogenic agent with a conventional chemotherapeutic agent.

Rheumatoid arthritis (RA) is one of the most common chronic autoimmune diseases. Despite considerable advances in clinical treatment of RA, suboptimal response to therapy and treatment discontinuation are still unresolved challenges due to systemic toxicity. It is of crucial importance to actively target and deliver therapeutic agents to inflamed joints in order to promote in situ activity and decrease systemic toxicity. In this study, we found that SPARC (secreted protein acidic and rich in cysteine) was overexpressed in the synovial fluid and synovium of RA patients as well as mice with collagen-induced arthritis (CIA), which has been scarcely reported. Building upon the SPARC signature of RA joint microenvironment and the intrinsic high affinity of SPARC for albumin, we fabricated methotrexate-loaded human serum albumin nanomedicines (MTX@HSA NMs) and explored them as biomimetic drug delivery systems for RA therapy. Upon intravenous injection of chlorin e6-labeled MTX@HSA NMs into CIA mice, the fluorescence/magnetic resonance dual-modal imaging revealed higher accumulations and longer retention of MTX@HSA NMs in inflamed joints with respect to free MTX molecules. In vivo therapeutic evaluations suggested that the MTX@HSA NMs were able to attenuate the progression of RA with better efficacy and fewer side effects even at half dose of administrated MTX in comparison with free MTX. By unraveling the mechanism driving the efficient accumulation of MTX@HSA NMs in RA joints and showing their ability to improve the safety and therapeutic efficacy of MTX, our work sheds light on the development of innovative anti-RA nanomedicines with a strong potential for clinical translation.

Combined cancer therapy possesses many advantages including improved tumoricidal efficacy, reduced side effects, and retarded drug resistance. Herein, a protein-polymer bioconjugate-coated multifunctional upconversion nanosystem, consisting of upconversion nanoparticles (UCNs) core, tailored amphiphilic protein-polymer bioconjugate shell, and photosensitizer zinc phthalocyanine (ZnPc) and antitumor drug doxorubicin coloaded inside, was elaborately developed for combined photodynamic therapy (PDT) and chemotherapy. In this system, UCNs core could convert deep penetrating near-infrared light to visible light for simultaneous cell fluorescence imaging and photodynamic therapy by activating ZnPc to generate cytotoxic ROS, while the protective shell of bovine serum albumin-poly(ε-caprolactone) (BSA-PCL) offered excellent water solubility, good stability, and low cytotoxicity. The ROS production test showed that this nanosystem could successfully generate singlet oxygen under NIR irradiation. A cellular uptake study demonstrated that intense fluorescence emission of the UCNs could be observed in HeLa cells, indicating their outstanding real-time imaging capability. More importantly, compared with single PDT or chemotherapy systems, the constructed combined therapy UCNs system demonstrated significantly enhanced tumor cell killing efficiency. On the basis of our findings, this multifunctional UCNs nanosystem could be a promising versatile theranostic nanoplatform for image-guided combined cancer therapy.

Many theranostic nanomedicines (NMs) have been fabricated by packaging imaging and therapeutic moieties together. However, concerns about their potential architecture instability and pharmacokinetic complexity remain major obstacles to their clinical translation. Herein, we demonstrated the use of CuInS/ZnS quantum dots (ZCIS QDs) as "all-in-one" theranostic nanomedicines that possess intrinsic imaging and therapeutic capabilities within a well-defined nanostructure. ZCIS QDs were exploited for multispectral optical tomography (MSOT) imaging and synergistic PTT/PDT therapy. Due to the intrinsic fluorescence/MSOT imaging ability of the ZCIS QDs, their size-dependent distribution profiles were successfully visualized at tumor sites in vivo. Our results showed that the smaller nanomedicines (ZCIS NMs-25) have longer tumor retention times, higher tumor uptake, and deeper tumor penetration than the larger nanomedicines (ZCIS NMs-80). The ability of ZCIS QDs to mediate photoinduced tumor ablation was also explored. Our results verified that under a single 660 nm laser irradiation, the ZCIS NMs had simultaneous inherent photothermal and photodynamic effects, resulting in high therapy efficacy against tumors. In summary, the ZCIS QDs as "all-in-one" versatile nanomedicines allow high therapeutic efficacy as well as noninvasively monitoring tumor site localization profiles by imaging techniques and thus hold great potential as precision theranostic nanomedicines.

Multi-modality imaging-guided cancer therapy is considered as a powerful theranostic platform enabling simultaneous precise diagnosis and treatment of cancer. However, recently reported multifunctional systems with multiple components and sophisticate structures remain major obstacles for further clinical translation. In this work, a single-photomolecular theranostic nanoplatform is fabricated via a facile nanoprecipitation strategy. By encapsulating a semiconductor oligomer (IT-S) into an amphiphilic lipid, water-dispersible IT-S nanoparticles (IT-S NPs) are prepared. The obtained IT-S NPs have a very simple construction and possess ultra-stable near-infrared (NIR) fluorescence (FL)/photoacoustic (PA) dual-modal imaging and high photothermal conversion efficiency of 72.3%. Accurate spatiotemporal distribution profiles of IT-S NPs are successfully visualized by NIR FL/PA dual-modal imaging. With the comprehensive in vivo imaging information provided by IT-S NPs, tumor photothermal ablation is readily realized under precise manipulation of laser irradiation, which greatly improves the therapeutic efficacy without any obvious side effects. Therefore, the IT-S NPs allow high tumor therapeutic efficacy under the precise guidance of FL/PA imaging techniques and thus hold great potential as an effective theranostic platform for future clinical applications.

Suboptimal intratumor accumulation and poorly controllable release of encapsulated drugs remain unresolved challenges hampering further advancement of nanomedicines in cancer therapy. Herein, we conceived near-infrared (NIR) laser-triggered transformable BiS@HSA/DTX multiple nanorods (mNRs), which were made of small bundles of bismuth sulfide nanorods (BiS NRs) coated with docetaxel (DTX)-inlaid human serum albumin (HSA). The BiS@HSA/DTX mNRs had a lateral size of approximately 100 nm and efficiently accumulated in the tumor microenvironment upon systemic administration in tumor-bearing nude mice. NIR laser irradiation of the tumor area caused rapid disassembly of the BiS@HSA/DTX mNRs into individual HSA-coated BiS nanorods (BiS@HSA iNRs) and triggered the release of DTX from the HSA corona, due to the local temperature increase generated by BiS NRs via the photothermal effect. The laser-induced transformation into BiS@HSA iNRs facilitated their penetration and increased the retention time in tumor. The spatiotemporal delivery behavior of the BiS@HSA/DTX mNRs could be monitored by photoacoustic/computed tomography dual-modal imaging in vivo. Furthermore, because of the excellent photothermal conversion properties of BiS NRs and laser-triggered DTX release from BiS@HSA/DTX mNRs, efficient tumor combinatorial therapy was achieved via concurrent hyperthermia and chemotherapy in mice treated with BiS@HSA/DTX mNRs upon NIR laser irradiation.

Efficient small interfering RNA (siRNA) delivery in the presence of serum is of crucial importance for effective gene therapy. Fluorinated vectors are considered to be attractive candidates for siRNA-mediated gene therapy because of their delivery efficacy in serum-containing media. However, the mechanisms driving the superior gene transfection behavior of fluorinated vectors are still not well-understood, and comprehensive investigations are warranted. Herein, we fabricated a library of perfluorooctanoyl fluoride-fluorinated (PFF-fluorinated) oligoethylenimines (fxOEIs, x is the PFF:OEI feeding ratio), which can readily form nanoassemblies (fxOEI NAs) capable of efficient siRNA delivery in cells cultured in medium both devoid of and supplemented with fetal bovine serum (FBS). The gene silencing test in serum-containing medium revealed that the f0.7OEI/siRNA NAs achieved a luciferase silencing of ∼88.4% in Luc-HeLa cells cultured in FBS-containing medium, which was almost 2-fold greater than the silencing...

Dual-modal imaging techniques have gained intense attention for their potential role in the dawning era of tumor early accurate diagnosis. Chelate-free robust dual-modal imaging nanoprobes with high efficiency and low toxicity are of essential importance for tumor targeted dual-modal in vivo imaging. It is still a crucial issue to endow Cd-free dual-modal nanoprobes with bright fluorescence as well as high relaxivity. Herein, a facile synthetic strategy was developed to prepare Gd-doped CuInS/ZnS bimodal quantum dots (GCIS/ZnS, BQDs) with optimized properties. The fluorescent properties of the GCIS/ZnS BQDs can be thoroughly optimized by varying reaction temperature, aging time, and ZnS coating. The amount of Gd precursor can be well-controlled to realize the optimized balance between the MR relaxivity and optical properties. The obtained hydrophobic GCIS/ZnS BQDs were surface engineered into aqueous phase with PEGylated dextran-stearyl acid polymeric lipid vesicles (PEG-DS PLVs). Upon the phase transfer, the hydrophilic GCIS/ZnS@PLVs exhibited pronounced near-infrared fluorescence as well as high longitudinal relaxivity (r1 = 9.45 mM(-1) S(-1)) in water with good colloidal stability. In vivo tumor-bearing animal experiments further verified GCIS/ZnS@PLVs could achieve tumor-targeted MR/fluorescence dual-modal imaging. No toxicity was observed in the in vivo and ex vivo experiments. The GCIS/ZnS@PLVs present great potential as bimodal imaging contrast agents for tumor diagnosis.

Inspired by the specificity of acid tumor microenvironment, we constructed a flexible charge-reversible near-infrared (NIR) fluorescence nanoprobe in response to tumor extracellular pH (pHe) for effective tumor-specific imaging. The nanoprobe consists of an NIR-emitted CuInS2/ZnS quantum dot (CIS/ZS QDs) core and a tailored lauric acid and 2,3-dimethylmaleic anhydride modified e-polylysine (epsilon-PL-g-LA/DMA) shell, which provides not only a dense protective layer for the QDs but also the ability of pHe-induced positive charge-mediated endocytosis into tumor cells. The results showed that the QDs@epsilon-PL-g-LA/DMA nanoprobe with a uniform size of 40 nm had high chemical stability at pH 7.4 and excellent optical properties. Especially, it swiftly reversed its surface charge to positive in 20 min when exposed to pHe due to the cleavage of the beta-carboxyl amide bond of epsilon-PL-g-LA/DMA. Moreover, the cell uptake of the pHe-sensitive QDs nanoprobe exposed at pH 6.8 into HeLa cells is much more significant than that at pH 7.4, which further verified the availability of the electrostatic adsorptive endocytosis facilitated targeting ability. The pHe-induced targeting imparted the QDs nanoprobe a broad targeting ability in a variety of solid tumors. Furthermore, as an effective alternative mechanism for tumor targeting, responsive charge reversion is also universally applicable to other cancer theranostics agent.

Organic dyes generally suffer from small Stokes shift that usually leads to self‐quenching and ‐gaining errors during the fluorescent imaging process. Here, a through‐bond energy transfer (TBET) cassette is developed with large Stokes shift to pursue precise cell imaging. The TBET is constructed by covalently conjugated tetraphenylethene (acts as donor) and rhodamine (acceptor) through an acetylene bond. The constructed TBET cassette distinctly behaves as dual‐Stokes shifts, including a large pseudo‐Stokes shift caused by energy transfer, from donor's absorption to acceptor's emission (up to 260 nm) and a smaller Stokes shift of acceptor molecules itself. Due to the intrinsic dual‐Stokes shifts, TBET cassette exhibits specific “dual distinct absorbances, single shared emission” properties, which can be excitated under two different laser channels. By colocalization of the imaging readouts of these two channels, the precisely “double checked” fluorescent imaging is achieved in living cells.

Activatable theranostic nanomedicines involved in photothermal therapy (PTT) have received constant attention as promising alternatives to traditional therapies in clinic. However, the theranostic nanomedicines widely suffer from instability and complicated nanostructures, which hamper potential clinical applications. Herein, we demonstrated a terrylenediimide (TDI)-poly(acrylic acid) (TPA)-based nanomedicine (TNM) platform used as an intrinsic theranostic agent. As an exploratory paradigm in seeking biomedical applications, TDI was modified with poly(acrylic acid)s (PAAs), resulting in eight-armed, star-like TPAs composed of an outside hydrophilic PAA corona and an inner hydrophobic TDI core. TNMs were readily fabricated via spontaneous self-assembly. Without additional vehicle and cargo, the as-prepared TNMs possessed a robust nanostructure and high photothermal conversion efficiency up to approximately 41%. The intrinsic theranostic properties of TNMs for use in photoacoustic (PA) imaging by a multispectral optoacoustic tomography system and in mediating photoinduced tumor ablation were intensely explored. Our results suggested that the TNMs could be successfully exploited as intrinsic theranostic agents for PA imaging-guided efficient tumor PTT. Thus, these TNMs hold great potential for (pre)clinical translational development.

Convenient and fast testing using an immunochromatography test strip (ICTS) enables rapid yes/no decisions regarding a disease to be made. However, the fundamental limitations of an ICTS, such as a lack of quantitative and sensitive analysis, severely hampers its application in reliable medical testing for the early detection of cancer. Herein, we overcame these limitations by integrating an ICTS with quantum dot nanobeads (QD nanobeads), which were fabricated by encapsulating QDs within modified poly(tert-butyl acrylate-co-ethyl acrylate-co-methacrylic acid) and served as a robust signal-generating reagent for the ICTS. Prostate specific antigen (PSA) was used as a model analyte to demonstrate the performance of the QD nanobeads-based ICTS platform. Under optimized conditions, the concentration of PSA could be determined within 15 min with high sensitivity and specificity using only 40 μL of sample. The detection limit was enhanced by ∼12-fold compared with that of an ICTS that used QDs encapsulated by commercial 11-mercaptoundecanoic acid (QDs@MUA) as the signal-generating reagent. At the same time, the possible clinical utility of this approach was demonstrated by measurements recorded from PSA-positive patient specimens. Our data suggest that the QD nanobeads-based ICTS platform is not only rapid and low-cost but also highly sensitive and specific for use in quantitative point-of-care diagnostics; thus, it holds promise for becoming a part of routine medical testing for the early cancer of detection.

Photothermal therapy (PTT) is attracting increasing interest and becoming more widely used for skin cancer therapy in the clinic, as a result of its noninvasiveness and low systemic adverse effects. However, there is an urgent need to develop biocompatible PTT agents, which enable accurate imaging, monitoring, and diagnosis. Herein, a biocompatible Gd-integrated CuS nanotheranostic agent (Gd:CuS@BSA) was synthesized via a facile and environmentally friendly biomimetic strategy, using bovine serum albumin (BSA) as a biotemplate at physiological temperature. The as-prepared Gd:CuS@BSA nanoparticles (NPs) with ultrasmall sizes (ca. 9 nm) exhibited high photothermal conversion efficiency and good photostability under near-infrared (NIR) laser irradiation. With doped Gd species and strong tunable NIR absorbance, Gd:CuS@BSA NPs demonstrate prominent tumor-contrasted imaging performance both on the photoacoustic and magnetic resonance imaging modalities. The subsequent Gd:CuS@BSA-mediated PTT result shows high therapy efficacy as a result of their potent NIR absorption and high photothermal conversion efficiency. The immune response triggered by Gd:CuS@BSA-mediated PTT is preliminarily explored. In addition, toxicity studies in vitro and in vivo verify that Gd:CuS@BSA NPs qualify as biocompatible agents. A biodistribution study demonstrated that the NPs can undergo hepatic clearance from the body. This study highlights the practicality and versatility of albumin-mediated biomimetic mineralization of a nanotheranostic agent and also suggests that bioinspired Gd:CuS@BSA NPs possess promising imaging guidance and effective tumor ablation properties, with high spatial resolution and deep tissue penetration.

A simple, straightforward, and reproducible strategy for the construction of a near-infrared (NIR) fluorescence nanoprobe was developed by coating CuInS2/ZnS quantum dots (CIS/ZnS QDs) with a novel amphiphilic bioconjugate. The amphiphilic bioconjugate with a tailor-designed structure of bovine serum albumin (BSA) as the hydrophilic segment and poly(ε-caprolactone) (PCL) as the hydrophobic part was fabricated by chemical coupling the hydrophobic polymer chain to BSA via the maleimide-sulfhydryl reaction. By incorporating CIS/ZnS QDs into the hydrophobic cores of the self-assembly of BSA-PCL conjugate, the constructed NIR fluorescence nanoprobe exhibited excellent fluorescent properties over a wide pH range (pH 3-10) and a good colloidal stability in PBS buffer (pH = 7.4) with or without 10% fetal bovine serum. The presence of the outer BSA shell effectively reduced the nonspecific cellular binding and imparted high biocompatibility and low-toxicity to the probe. Moreover, the NIR fluorescence nanoprobe could be functionalized by conjugating cyclic Arg-Gly-Asp (cRGD) peptide, and the decorated nanoprobe was shown to be highly selective for targeted integrin αvβ3-overexpressed tumor cell imaging. The feasibility of the constructed NIR fluorescence probe in vivo application was further investigated and the results demonstrated its great potential for in vivo imaging. This developed protocol for phase transfer of the CIS/ZnS QDs was universal and applicable to other nanoparticles stabilized with hydrophobic ligands.

Functionalized quantum dots (QDs) have been widely explored for multimodality bioimaging and proven to be versatile agents. Attaching positron-emitting radioisotopes onto QDs not only endows their positron emission tomography (PET) functionality, but also results in self-illuminating QDs, with no need for an external light source, by Cerenkov resonance energy transfer (CRET). Traditional chelation methods have been used to incorporate the radionuclide, but these methods are compromised by the potential for loss of radionuclide due to cleavage of the linker between particle and chelator, decomplexation of the metal, and possible altered pharmacokinetics of nanomaterials. Herein, we described a straightforward synthesis of intrinsically radioactive [(64)Cu]CuInS/ZnS QDs by directly incorporating (64)Cu into CuInS/ZnS nanostructure with (64)CuCl2 as synthesis precursor. The [(64)Cu]CuInS/ZnS QDs demonstrated excellent radiochemical stability with less than 3% free (64)Cu detected even after exposure to serum containing EDTA (5 mM) for 24 h. PEGylation can be achieved in situ during synthesis, and the PEGylated radioactive QDs showed high tumor uptake (10.8% ID/g) in a U87MG mouse xenograft model. CRET efficiency was studied as a function of concentration and (64)Cu radioactivity concentration. These [(64)Cu]CuInS/ZnS QDs were successfully applied as an efficient PET/self-illuminating luminescence in vivo imaging agents.

Inorganic nanoparticles have been introduced into biological systems as useful probes for in vitro diagnosis and in vivo imaging, due to their relatively small size and exceptional physical and chemical properties. A new kind of colortunable Gd-Zn-Cu-In-S/ZnS (GZCIS/ZnS) quantum dots (QDs) with stable crystal structure has been successfully synthesized and utilized for magnetic resonance (MR) and fluorescence dual modality imaging. This strategy allows successful fabrication of GZCIS/ZnS QDs by incorporating Gd into ZCIS/ZnS QDs to achieve great MR enhancement without compromising the fluorescence properties of the initial ZCIS/ZnS QDs. The as-prepared GZCIS/ZnS QDs show high T 1 MR contrast as well as “color-tunable” photoluminescence (PL) in the range of 550–725 nm by adjusting the Zn/Cu feeding ratio with high PL quantum yield (QY). The GZCIS/ZnS QDs were transferred into water via a bovine serum albumin (BSA) coating strategy. The resulting Cd-free GZCIS/ZnS QDs reveal negligible cytotoxicity on both HeLa and A549 cells. Both fluorescence and MR imaging studies were successfully performed in vitro and in vivo. The results demonstrated that GZCIS/ZnS QDs could be a dual-modal contrast agent to simultaneously produce strong MR contrast enhancement as well as fluorescence emission for in vivo imaging.