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Nutritional metal ions play critical roles in many important immune processes. Hence, the effective modulation of metal ions may open up new forms of immunotherapy, termed as metalloimmunotherapy. Here, we demonstrate a prototype of cancer metalloimmunotherapy using cyclic dinucleotide (CDN) stimulator of interferon genes (STING) agonists and Mn2+. We screened various metal ions and discovered specific metal ions augmented STING agonist activity, wherein Mn2+ promoted a 12- to 77-fold potentiation effect across the prevalent human STING haplotypes. Notably, Mn2+ coordinated with CDN STING agonists to self-assemble into a nanoparticle (CDN–Mn2+ particle, CMP) that effectively delivered STING agonists to immune cells. The CMP, administered either by local intratumoural or systemic intravenous injection, initiated robust anti-tumour immunity, achieving remarkable therapeutic efficacy with minute doses of STING agonists in multiple murine tumour models. Overall, the CMP offers a new platform for local and systemic cancer treatments, and this work underscores the great potential of coordination nanomedicine for metalloimmunotherapy. The stimulation of interferon genes (STING) pathway with STING agonists such as cyclic dinucleotides (CDNs) has emerged as a promising immunotherapeutic approach. Here, the authors show that Mn2+ can amplify the STING-promoted anti-tumour immune response in challenging murine tumour models by coordinating with CDNs and self-assembling into nanoparticles that can be delivered locally and systemically.

The host immune system possesses an intrinsic ability to target and kill cancer cells in a specific and adaptable manner that can be further enhanced by cancer immunotherapy, which aims to train the immune system to boost the antitumor immune response. Several different categories of cancer immunotherapy have emerged as new standard cancer therapies in the clinic, including cancer vaccines, immune checkpoint inhibitors, adoptive T cell therapy, and oncolytic virus therapy. Despite the remarkable survival benefit for a subset of patients, the low response rate and immunotoxicity remain the major challenges for current cancer immunotherapy. Over the last few decades, nanomedicine has been intensively investigated with great enthusiasm, leading to marked advancements in nanoparticle platforms and nanoengineering technology. Advances in nanomedicine and immunotherapy have also led to the emergence of a nascent research field of nano-immunotherapy, which aims to realize the full therapeutic potential of immunotherapy with the aid of nanomedicine. In particular, nanocarriers present an exciting opportunity in immuno-oncology to boost the activity, increase specificity, decrease toxicity, and sustain the antitumor efficacy of immunological agents by potentiating immunostimulatory activity and favorably modulating pharmacological properties. This review discusses the potential of nanocarriers for cancer immunotherapy and introduces preclinical studies designed to improve clinical cancer immunotherapy modalities using nanocarrier-based engineering approaches. It also discusses the potential of nanocarriers to address the challenges currently faced by immuno-oncology as well as the challenges for their translation to clinical applications.

The performance of immune checkpoint inhibitors, which benefit only a subset of patients and can cause serious immune-related adverse events, underscores the need for strategies that induce T-cell immunity with minimal toxicity. The gut microbiota has been implicated in the outcomes of patients following cancer immunotherapy, yet manipulating the gut microbiome to achieve systemic antitumour immunity is challenging. Here, we show, in multiple murine tumour models, that inulin — a widely consumed dietary fibre — formulated as a colon-retentive orally administered gel can effectively modulate the gut microbiome in situ, induce systemic memory-T-cell responses, and amplify the antitumour activity of the checkpoint inhibitor anti-programmed-cell-death-protein-1 (anti-PD-1). Orally delivered inulin-gel treatments increased the relative abundances of key commensal microbes and their short-chain-fatty-acid metabolites, and led to enhanced recall responses for interferon-γ+ CD8+ T cells as well as to the establishment of stem-like T-cell factor-1+ PD-1+ CD8+ T cells within the tumour microenvironment. Gels for the in situ modulation of the gut microbiome may be applicable more broadly to treat pathologies associated with a dysregulated gut microbiome., One-sentence editorial summary: An orally administered gel that is retained in the colon modulates the gut microbiome of mice with murine tumours, inducing systemic memory-T-cell responses, and amplifying the antitumour activity of a checkpoint inhibitor.

Major histocompatibility complex-I (MHC-I) presents tumour antigens to CD8+ T cells and triggers anti-tumour immunity. Humans may have 30,000–60,000 long noncoding RNAs (lncRNAs). However, it remains poorly understood whether lncRNAs affect tumour immunity. Here, we identify a lncRNA, lncRNA inducing MHC-I and immunogenicity of tumour (LIMIT), in humans and mice. We found that IFNγ stimulated LIMIT, LIMIT cis-activated the guanylate-binding protein (GBP) gene cluster and GBPs disrupted the association between HSP90 and heat shock factor-1 (HSF1), thereby resulting in HSF1 activation and transcription of MHC-I machinery, but not PD-L1. RNA-guided CRISPR activation of LIMIT boosted GBPs and MHC-I, and potentiated tumour immunogenicity and checkpoint therapy. Silencing LIMIT, GBPs and/or HSF1 diminished MHC-I, impaired antitumour immunity and blunted immunotherapy efficacy. Clinically, LIMIT, GBP- and HSF1-signalling transcripts and proteins correlated with MHC-I, tumour-infiltrating T cells and checkpoint blockade response in patients with cancer. Together, we demonstrate that LIMIT is a cancer immunogenic lncRNA and the LIMIT–GBP–HSF1 axis may be targetable for cancer immunotherapy. Li et al. identify LIMIT as a lncRNA that modulates MHC-I expression through HSP90 and HSF1, thereby regulating antitumour immune response and the efficacy of immunotherapy.

The current health crisis of corona virus disease 2019 (COVID-19) highlights the urgent need for vaccine systems that can generate potent and protective immune responses. Protein vaccines are safe, but conventional approaches for protein-based vaccines often fail to elicit potent and long-lasting immune responses. Nanoparticle vaccines designed to co-deliver protein antigens and adjuvants can promote their delivery to antigen-presenting cells and improve immunogenicity. However, it remains challenging to develop vaccine nanoparticles that can preserve and present conformational epitopes of protein antigens for induction of neutralizing antibody responses. Here, we have designed a new lipid-based nanoparticle vaccine platform (NVP) that presents viral proteins (HIV-1 and SARS-CoV-2 antigens) in a conformational manner for induction of antigen-specific antibody responses. We show that NVP was readily taken up by dendritic cells (DCs) and promoted DC maturation and antigen presentation. NVP loaded with BG505.SOSIP.664 (SOSIP) or SARS-CoV-2 receptor-binding domain (RBD) was readily recognized by neutralizing antibodies, indicating the conformational display of antigens on the surfaces of NVP. Rabbits immunized with SOSIP-NVP elicited strong neutralizing antibody responses against HIV-1. Furthermore, mice immunized with RBD-NVP induced robust and long-lasting antibody responses against RBD from SARS-CoV-2. These results suggest that NVP is a promising platform technology for vaccination against infectious pathogens., Graphical abstract A nanoparticle vaccine platform that preserves conformational epitopes of protein antigens elicits robust humoral immune responses against HIV-1 and SARS-CoV-2.Unlabelled Image, Highlights • Vaccine nanoparticles effectively deliver antigens to dendritic cells in draining lymph nodes. • Vaccine nanoparticles allow conformational display of viral antigens from HIV-1 or SARS-CoV-2. • Vaccine nanoparticles elicit strong neutralizing antibody responses against HIV-1 in rabbits. • Vaccine nanoparticles induce robust and long-lasting antibody responses against SARS-CoV-2 in mice.

Cancer stem cells (CSCs) proliferate extensively and drive tumor metastasis and recurrence. CSCs have been identified in over 20 cancer types to date, but it remains unknown how to target and eliminate CSCs in vivo. Aldehyde dehydrogenase (ALDH) is a marker that has been used extensively for isolating CSCs. Here we present a novel approach to target and reduce the frequency of ALDH(high) CSCs by vaccination against ALDH. We have identified ALDH1-A1 and ALDH1-A3 epitopes from CSCs and developed synthetic high-density lipoprotein nanodiscs for vaccination against ALDH(high) CSCs. Nanodiscs increased antigen trafficking to lymph nodes and generated robust ALDH-specific T cell responses. Nanodisc vaccination against ALDH(high) CSCs combined with anti-PD-L1 therapy exerted potent antitumor efficacy and prolonged animal survival in multiple murine models. Overall, this is the first demonstration of a simple nanovaccine strategy against CSCs and may lead to new avenues for cancer immunotherapy against CSCs.

Innate immune cells recognize and respond to pathogen-associated molecular patterns. In particular, polysaccharides found in the microbial cell wall are potent activators of dendritic cells (DCs). Here, we report a new class of nanocapsules, termed sugar-capsules, entirely composed of polysaccharides derived from the microbial cell wall. We show that sugar-capsules with a flexible polysaccharide shell and a hollow core efficiently drain to lymph nodes and activate DCs. In particular, sugar-capsules composed of mannan (Mann-capsule) carrying mRNA (mRNA) promote strong DC activation, mRNA translation, and antigen presentation on DCs. Mann-capsules elicit robust antigen-specific CD4+ and CD8α+ T-cell responses with antitumor efficacy in vivo. The strategy presented in this study is generally applicable for utilizing pathogen-derived molecular patterns for vaccines and immunotherapies.

Photodynamic therapy (PDT) is an effective, noninvasive therapeutic modality against local tumors that are accessible to the source of light. However, it remains challenging to apply PDT for the treatment of disseminated, metastatic cancer. On the other hand, cancer immunotherapy offers a promising approach for generating systemic antitumor immune responses against disseminated cancer. Here we report a multifunctional nanomaterial system for the combination of PDT and personalized cancer immunotherapy and demonstrate their potency against local as well as disseminated tumors. Specifically, we have synthesized uniform and biodegradable mesoporous silica nanoparticles (bMSN) with an average size of ~80 nm and large pore size of 5–10 nm for theranostic positron emission tomography (PET)-guided PDT and neoantigen-based cancer vaccination. Multiple neoantigen peptides, CpG oligodeoxynucleotide adjuvant, and photosensitizer chlorin e6 were coloaded into a bMSN nanoplatform, and PET imaging revealed effective accumulation of bMSN in tumors (up to 9.0% ID/g) after intravenous administration. Subsequent PDT with laser irradiation recruited dendritic cells to PDT-treated tumor sites and elicited neoantigen-specific, tumor-infiltrating cytotoxic T-cell lymphocytes. Using multiple murine models of bilateral tumors, we demonstrate strong antitumor efficacy of PDT-immunotherapy against locally treated tumors as well as distant, untreated tumors. Our findings suggest that the bMSN is a promising platform for combining imaging and PDT-enhanced personalized immunotherapy for the treatment of advanced cancer.

Cancer immunotherapy is revolutionizing oncology. However, dose-limiting toxicities and low patient response rates remain major challenges in the clinic. Cancer nanomedicine in combination with immunotherapies offers the possibility to amplify antitumour immune responses and to sensitize tumours to immunotherapies in a safe and effective manner. In this Review, we discuss opportunities for combination immunotherapy based on nanoparticle platforms designed for chemotherapy, photothermal therapy, photodynamic therapy, radiotherapy and gene therapy. We highlight how nanoparticles can be used to reprogramme the immunosuppressive tumour microenvironment and to trigger systemic antitumour immunity, synergizing with immunotherapies against advanced cancer. Finally, we discuss strategies to improve tumour and immune cell targeting while minimizing toxicity and immune-related adverse events, and we explore the potential of theranostic nanoparticles for combination immunotherapy. Cancer nanomedicine in combination with immunotherapies offers the possibility to amplify antitumour immune responses and to sensitize tumours to immunotherapies. In this Review, the authors discuss combination immunotherapy based on nanoparticle platforms designed for chemotherapy, photothermal therapy, photodynamic therapy, radiotherapy and gene therapy.

Conventional cancer vaccines based on soluble vaccines and traditional adjuvants have produced suboptimal therapeutic efficacy in clinical trials. Thus, there is an urgent need for vaccine technologies that can generate potent T cell responses with strong anti-tumor efficacy. We have previously reported the development of synthetic high-density protein (sHDL) nanodiscs for efficient lymph node (LN)-targeted co-delivery of antigen peptides and CpG oligonucleotides (a Toll-like receptor-9 agonist). Here, we performed a comparative study in mice and non-human primates (NHPs) to identify an ideal vaccine platform for induction of CD8+ T cell responses. In particular, we compare the efficacy of CpG class B, CpG class C, and polyICLC (a synthetic double-stranded RNA analog, a TLR-3 agonist), each formulated with antigen-carrying sHDL nanodiscs. Here, we report that sHDL-Ag admixed with polyICLC elicited robust Ag-specific CD8+ T cell responses in mice, and when used in combination with α-PD-1 immune checkpoint inhibitor, sHDL-Ag + polyICLC completely eliminated large established (~100 mm(3)) MC-38 tumors in mice. Moreover, sHDL-Gag + polyICLC induced robust Simian immunodeficiency virus Gag-specific, polyfunctional CD8+ T cell responses in rhesus macaques and could further amplify the efficacy of recombinant adenovirus-based vaccine. Notably, while both sHDL-Ag-CpG-B and sHDL-Ag-CpG-C generated strong Ag-specific CD8+ T cell responses in mice, their results were mixed in NHPs. Overall, sHDL combined with polyICLC offers a strong platform to induce CD8+ T cells for vaccine applications.

The effectivity of cancer immunotherapies is hindered by immunosuppressive tumour microenvironments that are poorly infiltrated by effector T cells and natural killer cells. In infection and autoimmune disease, the recruitment and activation of effector immune cells is coordinated by pro-inflammatory T helper 17 (T

Nanoparticles (NPs) can serve as a promising vaccine delivery platform for improving pharmacological property and codelivery of antigens and adjuvants. However, NP‐based vaccines are generally associated with complex synthesis and postmodification procedures, which pose technical and manufacturing challenges for tailor‐made vaccine production. Here, modularly programmed, polyethyleneimine (PEI)‐based NP vaccines are reported for simple production of personalized cancer vaccines. Briefly, PEI is conjugated with neoantigens by facile coupling chemistry, followed by electrostatic assembly with CpG adjuvants, leading to the self‐assembly of nontoxic, sub‐50 nm PEI NPs. Importantly, PEI NPs promote activation and antigen cross‐presentation of antigen‐presenting cells and cross‐priming of neoantigen‐specific CD8+ T cells. Surprisingly, after only a single intratumoral injection, PEI NPs with optimal PEGylation elicit as high as ≈30% neoantigen‐specific CD8+ T cell response in the systemic circulation and sustain elevated CD8+ T cell response over 3 weeks. PEI‐based nanovaccines exert potent antitumor efficacy against pre‐established local tumors as well as highly aggressive metastatic tumors. PEI engineering for modular incorporation of neoantigens and adjuvants offers a promising strategy for rapid and facile production of personalized cancer vaccines., Modularly programmed, polyethyleneimine (PEI)‐based nanoparticle (NP) vaccines are developed for simple production of personalized cancer vaccines. PEI‐antigen conjugates and CpG adjuvants are mixed form nontoxic, sub‐50 nm PEI NPs. PEI NPs elicit strong, long‐lasting neoantigen‐specific CD8+ T cell response with potent antitumor efficacy against local as well as metastatic tumors. PEI NPs offer a promising strategy for personalized cancer vaccination.

Assembled AuNPs in a DNA hydrogel (Dgel) showed strongly coupled plasmon modes, and the Dgel vehicle can co-load anticancer drugs such as doxorubicin (Dox) as a light-controlled releasing cargo by DNA intercalations. Upon laser excitation, local heat shock generation was accompanied by the release of Dox. A highly synergistic combination of thermo- and chemotherapy was demonstrated in cellular and animal models. Our Dgel vehicle can be fragmented after the excitation-induced heat generations, which subsequently causes the dispersion of the AuNPs. Our system may be less toxic because it uses small sizes of AuNPs, and the inherently biocompatible scaffold may reduce the long-term toxicity by rapid clearance.

Nanomaterials offer unique advantages as drug-delivery vehicles for cancer therapeutics. For immuno-oncology applications, cancer nanomedicine should be developed beyond drug-delivery platforms. A greater emphasis on actively modulating host anticancer immunity using nanomaterials provides new avenues for developing novel cancer therapeutics.

Photothermal therapy (PTT) and neoantigen cancer vaccine each offers minimally invasive and highly specific cancer therapy; however, they are not effective against large established tumors due to physical and biological barriers that attenuate thermal ablation and abolish anti-tumor immunity. Here, we designed and performed comparative study using small (~ 50 mm(3)) and large (> 100 mm(3)) tumors to examine how tumor size affects the therapeutic efficiency of PTT and neoantigen cancer vaccine. We show that spiky gold nanoparticle (SGNP)-based PTT and synergistic dual adjuvant-based neoantigen cancer vaccine can efficiently regress small tumors as a single agent, but not large tumors due to limited internal heating and immunosuppressive tumor microenvironment (TME). We report that PTT sensitizes tumors to neoantigen cancer vaccination by destroying and compromising the TME via thermally induced cellular and molecular damage, while neoantigen cancer vaccine reverts local immune suppression induced by PTT and shapes residual TME in favor of anti-tumor immunity. The combination therapy efficiently eradicated large local tumors and also exerted strong abscopal effect against pre-established distant tumors with robust systemic anti-tumor immunity. Thus, PTT combined with neoantigen cancer vaccine is a promising nano-immunotherapy for personalized therapy of advanced cancer.

Identification of tumor-specific mutations, called neoantigens, offers new exciting opportunities for personalized cancer immunotherapy . However, it remains challenging to achieve robust induction of neoantigen-specific T cells and drive their infiltration into the tumor microenvironment (TME). Here, we have developed a novel polyethyleneimine (PEI)-based personalized vaccine platform carrying neoantigen peptides and CpG adjuvants in a compact nanoparticle (NP) for their spatio-temporally concerted delivery. The NP vaccine significantly enhanced activation and antigen cross-presentation of dendritic cells, resulting in strong priming of neoantigen-specific CD8 + T cells with the frequency in the systemic circulation reaching as high as 23 ± 7% after a single subcutaneous administration. However, activated CD8 + T cells in circulation exhibited limited tumor infiltration, leading to poor anti-tumor efficacy. Notably, local administration of stimulator of interferon genes (STING) agonist promoted tumor infiltration of vaccine-primed CD8 + T cells, thereby overcoming one of the major challenges in achieving strong anti-tumor efficacy with cancer vaccination. The NP vaccination combined with STING agonist therapy eliminated tumors in murine models of MC-38 colon carcinoma and B16F10 melanoma and established long-term immunological memory . Our approach provides a novel therapeutic strategy based on combination nano-immunotherapy for personalized cancer immunotherapy.

Herein, we show that DNA nanostructures have great potential as templates for the synthesis of shape-controlled metal nanostructures. In specific, branch-shaped gold nanostructures, which show broad absorption in near the infrared region and have high efficacy in photothermal cancer cell treatment, have been successfully synthesized by using X-shaped and Y-shaped DNA as templates.

We report a new nanoparticle system for chemoimmunotherapy that elicits robust antitumor immunity against established tumors., Although immune checkpoint blockade has shown initial success for various cancers, only a small subset of patients benefits from this therapy. Some chemotherapeutic drugs have been reported to induce antitumor T cell responses, prompting a number of clinical trials on combination chemoimmunotherapy. However, how to achieve potent immune activation with traditional chemotherapeutics in a manner that is safe, effective, and compatible with immunotherapy remains unclear. We show that high-density lipoprotein–mimicking nanodiscs loaded with doxorubicin (DOX), a widely used chemotherapeutic agent, can potentiate immune checkpoint blockade in murine tumor models. Delivery of DOX via nanodiscs triggered immunogenic cell death of cancer cells and exerted antitumor efficacy without any overt off-target side effects. “Priming” tumors with DOX-carrying nanodiscs elicited robust antitumor CD8+ T cell responses while broadening their epitope recognition to tumor-associated antigens, neoantigens, and intact whole tumor cells. Combination chemoimmunotherapy with nanodiscs plus anti–programmed death 1 therapy induced complete regression of established CT26 and MC38 colon carcinoma tumors in 80 to 88% of animals and protected survivors against tumor recurrence. Our work provides a new, generalizable framework for using nanoparticle-based chemotherapy to initiate antitumor immunity and sensitize tumors to immune checkpoint blockade.

The present work illustrates unique design, construction and operation of an i-motif-based DNA nanomachine templated on gold nanoparticles (AuNPs), which utilizes pH-responsive dynamic motion of i-motif DNA strands and aggregational behavior of AuNPs to elicit programmed delivery of therapeutic siRNA. The pH-sensitive nucleic acids immobilized on the AuNPs consisted of three functional segments, i.e., an i-motif DNA, an overhanging linker DNA and a therapeutic siRNA. At neutral pH, the i-motif DNA is hybridized with the overhanging linker DNA segment of the therapeutic siRNA. However, in endosomal acidic pH, the i-motif DNA forms interstrand tetraplex, which could induce cluster formation of AuNPs resulting in endosomal escape of AuNP clusters, and produce a high gene silencing efficiency by releasing siRNA in the cytosol. Furthermore, the cluster formation of AuNPs accelerated photothermal ablation of cells when irradiated with laser. Precise and synchronized biomechanical motion in subcellular microenvironment is realized through judicious integration of pH-responsive behavior of the i-motif DNA and AuNPs, and meticulous designing of DNA.

A small (sub 6 nm hydrodynamic size) and pH-responsive gold nanoparticle photothermal agent is reported, which can respond to changes in pH and form aggregates. The coupled plasmon mode of aggregates can be efficiently exploited for photothermal cancer therapy using longer excitation wavelength.

We report a nanoparticle-based probe that can be used for a "turn-on" theragnostic agent for simultaneous Raman imaging/diagnosis and photothermal therapy. The agent consists of a 10 nm spherical gold nanoparticle (NP) with pH-responsive ligands and Raman probes on the surface. They are engineered to exhibit the surface with both positive and negative charges upon mildly acidic conditions, which subsequently results in rapid aggregations of the gold NPs. This aggregation simultaneously provides hot spots for the SERS probe with the enhancement factor reaching 1.3 × 10(4) and shifts the absorption to far-red and near-infrared (which is optimal for deep tissue penetration) by the coupled plasmon resonances; this shift was successfully exploited for low-threshold photothermal therapy. The theragnostic gold NPs are cancer-specific because they aggregate rapidly and accumulate selectively in cancerous cells. As the result, both Raman imaging and photothermal efficacy were turned on under a cancerous local environment. In addition, the relatively small hydrodynamic size can have the potential for better access to targeted delivery in vivo and facilitated excretion after therapy.

A new type of quantum dot (QD) ligand chemistry is introduced that can provide positive, negative, or zwitterionic surface QDs. CdSe/CdZnS core-shell QDs are decorated with ligands, and the non-specific and specific interactions of the QDs through their surface charge are investigated with the focus on cellular adsorptions and endocytosis. Zwitterionic QDs are compact with a ligand hydrodynamic thickness of less than 2 nm, they are colloidally very stable over a broad pH range and even in saturated NaCl solution, and they show minimal non-specific adsorptions. Positive and negative QDs show a very different behavior for cellular adsorption and subsequent incorporation, suggesting mostly energy-independent pathways for positive QDs and exclusively adenosine triphosphate (ATP)-dependent pathways for negative QDs. The zwitterionic QD surface ligands can also be used in conjunction with other functional groups, which allows simple conjugations for highly specific targeting whereas retaining the advantages of a zwitterionic QD surface. This QD surface chemistry can provide highly specific and very sensitive imaging with very low background level. Using the mixed QD surface ligand system, we demonstrated streptavidin and antibody QD conjugates that show a signal-to-noise ratio that is over 4000 times higher than the unconjugated mixture, which was used as a control case. The QD chemistry reported herein can be easily extended to other functional groups, such as alkynes, azides, or other amines, and can be further used in many future applications, including single-QD level experiments, sensitive assays, or in vivo applications using anti-fouling QD probes.

Strongly luminescent and highly loaded CdSe quantum dot (QD)−silica composite films are prepared by a simple one-step method. QDs are grown in situ as the silica matrix forms from spin-on-glass organosiloxane polymers. The nucleation and growth of QDs in the silica matrix is directly observed using TEM. The QD composites are comprehensively characterized, which includes photoluminescence(PL) decay, PL efficiency, and QD volume fraction. The QD emission can span the entire visible range and can be tuned by the preparation condition. The PL of QDs is very strong, reaching the quantum efficiency up to 35%. Very high QD loading is achieved with the volume fraction as high as 13%, which makes our composite the highest loaded QD−silica composite material. We further showcase the versatile applicability of our method by a QD−silica composite capped down-conversion pseudo white LED.

Synthesis of a size series of colloidal ZnTe/ZnSe (core/shell) quantum dots (QDs) is reported. Because of the unique Type-II characters, their emission can range over an extended wavelength regime, showing photoluminescence (PL) from blue to amber. The PL lifetime measures as long as 77 ns, which clearly indicates the Type-II characteristics. ZnTe/ZnSe (Core/Shell) QDs can be further passivated by ZnS layers, rendered in water, while preserving the optical and chemical stabilities and thus proved their potentials toward “nontoxic” biological or medical applications that are free from concerns regarding heavy-metal leakage. ZnTe/ZnSe Type-II QD/polymer hybrid organic solar cells are also showcased, promising environmentally friendly photovoltaic devices. ZnTe/ZnSe Type-II QD incorporated photovoltaic devices show 11 times higher power conversion efficiency, when compared to that of the control ZnSe QD devices. This results from the Type-II characteristic broad QD absorption up to extended wavelengths and t...

True colors: High-quality InP and InP/ZnS quantum dots (QDs) are obtained by means of a simple one-pot method in the presence of polyethylene glycol (PEG). Rapid and size-controlled reactions lead to highly crystalline and nearly monodisperse QDs at relatively low temperatures. The particles emit from cyan blue to far-red, and are successfully used in cellular imaging (see figure).

We report photoluminescence (PL) spectral switching of quantum dots (QDs) by chemically controlling transfers of electrons in and out of the type-II heterostructures. When electron charged, CdTe/CdSe (core/shell) QDs show huge PL blue shifts (up to ∼100 nm) whereas PL of CdSe/CdTe (core/shell) QDs red-shifts. We demonstrate reversible spectral switching of type-II QDs by repeated charging and neutralization processes. The PL spectral shifts are due to the interactions between injected spectrator electrons and type-II character excitons. Electron charged CdTe/CdSe QDs show PL blue shifts because of the strong repulsions between the shell-localized excitonic electrons and injected spectrator electrons. It is opposite for CdSe/CdTe QDs, where injected electrons in surface states attract the holes in the shells. We investigate the interactions of spectrator electrons and excitons as varying the dimensions of type-II QDs. We also compare the type-II QDs with type-I QDs such as CdSe, CdTe, and CdTeSe alloyed QD...

A series of quantum dot (QD) ligands are reported that can make strong polyelectrolyte QD surfaces with sulfonates or quaternary ammoniums, which can endow QDs with excellent colloidal stability independent of the pH and ionic strength, minimal hydrodynamic size, and can be exploited to achieve stable and flexible bioconjugations and layer-by-layer assembly.

Gold nanoparticles (AuNPs) are attractive photothermal agents for cancer therapy because they show efficient local heating upon excitation of surface plasmon oscillations. The strong absorption, efficient heat conversion, high photostability, inherent low toxicity and well-defined surface chemistry of AuNPs contribute to the growing interest in their photothermal therapy (PTT) applications. The facile tunability of gold nanostructures enables engineering of AuNPs for superior near-infrared photothermal efficacy and target selectivity, which guarantee efficient and deep tissue-penetrating PTT with mitigated concerns regarding side effects by nonspecific distributions. This article discusses the current research findings with representative near-infrared-active AuNPs, which include nanoshell, nanorod, nanocage, nanostar, nanopopcorn and nanoparticle assembly systems. AuNPs successfully demonstrate potential for use in PTT, but several hurdles to clinical applications remain, including long-term toxicity and a need for sophisticated control over biodistribution and clearance. Future research directions are discussed, especially regarding the clinical translation of AuNP photosensitizers.

We report a pH-responsive gold nanoparticles-in-liposome hybrid nanostructure, which effectively combines the pH-responsive assembly and surface plasmon property changes of 'smart' gold nanoparticles and enhanced systemic circulation and tumor accumulation of the PEG-grafted liposomes.

A combined two-photon microscopy (TPM) and angiographic optical coherence tomography (OCT) is developed, which can provide molecular, cellular, structural, and vascular information of tissue specimens in vivo. This combined system is implemented by adding an OCT vasculature visualization method to the previous combined TPM and OCT, and then is applied to in vivo tissue imaging. Two animal models, a mouse brain cranial window model and a mouse ear cancer model, are used. Both molecular, cellular information at local regions of tissues, and structural, vascular information at relatively larger regions are visualized in the same sections. In vivo tissue microenvironments are better elucidated by the combined TPM and angiographic OCT.

A challenge in using plasmonic nanostructure-drug conjugates for thermo-chemo combination cancer therapy lies in the huge size discrepancy; the size difference can critically differentiate their biodistributions and hamper the synergistic effect. Properly tuning the plasmonic wavelength for photothermal therapy typically results in the nanostructure size reaching ∼100 nm. We report a new combination cancer therapy platform that consists of relatively small 10 nm pH-responsive spherical gold nanoparticles and conjugated doxorubicins. They are designed to form aggregates in mild acidic environment such as in a tumor. The aggregates serve as a photothermal agent that can selectively exploit external light by their collective plasmon modes. Simultaneously, the conjugated doxorubicins are released. The spatiotemporal concertion is confirmed at the subcellular, cellular, and organ levels. Both agents colocalize in the cell nuclei. The conjugates accumulate in cancer cells by the rapid phagocytic actions and effective blockage of exocytosis by the increased aggregate size. They also effectively accumulate in tumors up to 17 times over the control because of the enhanced permeation and retention. The conjugates exhibit a synergistic effect enhanced by nearly an order of magnitude in cellular level. The synergistic effect is demonstrated by the remarkable reductions in both the therapeutically effective drug dosage and the photothermal laser threshold. Using an animal model, effective tumor growth suppression is demonstrated. The conjugates induce apoptosis to tumors without any noticeable damage to other organs. The synergistic effect in vivo is confirmed by qRT-PCR analysis over the thermal stress and drug-induced growth arrest.

Hot gold: The photothermal response upon pulsed laser irradiation is studied for pH-responsive gold-nanoparticle aggregates and compared to that of gold nanorods. The aggregates show a slight red shift in the absorption spectrum and retain the photothermal effect, whereas the nanorods lose the photothermal effect and exhibit a stark blue shift in the absorption.

Many kinds of inorganic nanoparticles (NPs) including semiconductor, metal, metal oxide, and lanthanide-doped NPs have been developed for imaging and therapy applications. Their unique optical, magnetic, and electronic properties can be tailored by controlling the composition, size, shape, and structure. Interaction of such NPs with cells and/or in vivo compartments is critically determined by the surface properties, and sophisticated control over the NP surface is essential to control their fate in biological environments. We review NP surface coating strategies using the categories of small surface ligand, polymer, and lipid. Use of small ligand molecules has the advantage of maintaining the minimal hydrodynamic (HD) size. Polymers can be advantageous in NP anchoring by combining multiple affinity groups. Encapsulation of NPs in polymers, lipids or surfactants can preserve the as-synthesized NPs. NP surface properties and reaction conditions should be carefully considered to obtain a bioconjugate that maintains the physicochemical properties of NP and functionalities of the conjugated biomolecules. We highlight how the surface properties of NPs impact their interactions with cells and in vivo compartments, especially focused on the important surface design parameters such as HD size, surface charge, and targeting. Typically, maximal cellular uptake can take place in the intermediate NP size range of 40-60nm. Clearance of NPs from blood circulation is largely dependent on the degree of uptake by reticuloendothelial system when they are larger than 10nm. When the HD size is below 10nm, NPs show broad distribution over many organs. Reduction of HD size below the limit of renal barrier can achieve fast clearance of NPs. For maximal tumor accumulation, NPs should have long blood circulation time and should be large enough to prevent rapid penetration. NPs are also desired to rapidly clear out from the body after the mission before they cause toxic side effects. However, efficient clearance from the body to avoid side effects may result in the reduction in residence time required for accumulation in target tissues. Smart design of NP surface coating that can meet the conflicting demands can open a new avenue of NP applications. Surface charge and hydrophobicity need to be carefully considered for NP surface design. Positively charged NPs more adsorb on cell membranes and consequently show higher level of internalizations when compared with negatively charged or neutral NPs. NPs encounter a large variety of biomolecules in vivo, where non-specific adsorptions can potentially alter the physicochemical properties of the NPs. For optimal performance, NPs are suggested to have neutral surface charge at physiological conditions, small HD size, and minimal non-specific adsorption levels. Zwitterionic NP surface coating by small surface ligands can be a promising approach. Toxicity is one of most critical issues, where proper control of the NP surface can significantly reduce the toxicities.

A simple and novel electrostatic coupling method is reported, which provides a hyaluronic acid−quantum dot conjugate (HA−QD) that is colloidally stable and size-tunable from 50 to 120 nm. The HA−QDs show cancer targeting efficiency, which suggests diagnostic and imaging applications. The conjugates are also demonstrated for the fluorescence staining capability for lymphatic vessels in vitro and in vivo. Using the HA−QDs in a small animal model, lymphatic vessels are visualized real-time in vivo for days. Comprehensive cytotoxicity evaluations are made for the conjugates and the unconjugated counterpart. The HA−QDs showcase the potentials toward cancer imaging and real-time visualization of changes in lymphatic vessels such as lymphangiogenesis.

We report the feasibility of a novel contrast agent, namely "smart" gold nanoparticles (AuNPs), in the detection of cancer cells with photothermal optical coherence tomography (PT-OCT). "Smart" AuNPs form aggregation in low pH condition, which is typical for cancer cells, and this aggregation results in a shift of their absorption spectrum. A PT-OCT system was developed to detect this pH-induced aggregation by combining an OCT light source and a laser with 660 nm in wavelength for photothermal excitation. Optical detection of pH-induced aggregation was tested with solution samples at two different pH conditions. An increase in optical path length (OPL) variation was measured at mild acidic condition, while there was not much change at neutral condition. Detection of cancer cells was tested with cultured cell samples. HeLa and fibroblast cells, as cancer and normal cells respectively, were incubated with "smart" gold nanoparticles and measured with PT-OCT. An elevated OPL variation signal was detected with the HeLa cells while not much of a signal was detected with the fibroblast cells. With the novel optical property of "smart" AuNPs and high sensitivity of PT-OCT, this technique is promising for cancer cell detection.

A new type of quantum dot (QD) ligand chemistry is introduced that can provide positive, negative, or zwitterionic surface QDs. CdSe/CdZnS core-shell QDs are decorated with ligands, and the non-specific and specific interactions of the QDs through their surface charge are investigated with the focus on cellular adsorptions and endocytosis. Zwitterionic QDs are compact with a ligand hydrodynamic thickness of less than 2 nm, they are colloidally very stable over a broad pH range and even in saturated NaCl solution, and they show minimal non-specific adsorptions. Positive and negative QDs show a very different behavior for cellular adsorption and subsequent incorporation, suggesting mostly energy-independent pathways for positive QDs and exclusively adenosine triphosphate (ATP)-dependent pathways for negative QDs. The zwitterionic QD surface ligands can also be used in conjunction with other functional groups, which allows simple conjugations for highly specific targeting whereas retaining the advantages of a zwitterionic QD surface. This QD surface chemistry can provide highly specific and very sensitive imaging with very low background level. Using the mixed QD surface ligand system, we demonstrated streptavidin and antibody QD conjugates that show a signal-to-noise ratio that is over 4000 times higher than the unconjugated mixture, which was used as a control case. The QD chemistry reported herein can be easily extended to other functional groups, such as alkynes, azides, or other amines, and can be further used in many future applications, including single-QD level experiments, sensitive assays, or in vivo applications using anti-fouling QD probes.