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Biomolecule-based nanostructures are inherently multifunctional and harbour diverse biological activities, which can be explored for cancer nanomedicine. The supramolecular properties of biomolecules can be precisely programmed for the design of smart drug delivery vehicles, enabling efficient transport in vivo, targeted drug delivery and combinatorial therapy within a single design. In this Review, we discuss biomolecule-based nanostructures, including polysaccharides, nucleic acids, peptides and proteins, and highlight their enormous design space for multifunctional nanomedicines. We identify key challenges in cancer nanomedicine that can be addressed by biomolecule-based nanostructures and survey the distinct biological activities, programmability and in vivo behaviour of biomolecule-based nanostructures. Finally, we discuss challenges in the rational design, characterization and fabrication of biomolecule-based nanostructures, and identify obstacles that need to be overcome to enable clinical translation., Multifunctional nanostructures are explored for smart cancer nanomedicine. This Review discusses nanostructures made of biomolecules, including polysaccharides, nucleic acids, peptides and proteins, which are inherently multifunctional and allow the targeting and delivery of cancer drugs to tumour tissue.

Local surface plasmon resonance (LSPR)-enhanced catalysis has attracted much attention recently. Palladium nanoparticles have been reported to have various nanozyme activities and exhibit promising potentials for biomedical applications. However, as Pd is a poor plasmonic metal, little attention has been paid to its LSPR-regulated nanozyme activity. Herein, by using Au nanorods (AuNRs) as a strong plasmonic core, we coated a thin layer Pd to form a rod-shaped core-shell structure. The obtained Au@PdNRs showed tunable LSPR bands in the near-infrared (NIR) spectral range inheriting from the Au core and yet an exposed Pd surface for catalysis. The oxidase-like activity was investigated in the dark and upon SPR excitation. The plasmon-enhanced activity was observed and was mainly ascribed to the local photothermal effect. Finally, to enhance biocompatibility, mesoporous silica-coated nanorods were used to detect the oxidase-like activity in cells. After being endocytosed by cells, upon plasmon excitation, the oxidase activity of Au@PdNRs could be manifested and lead to higher cytotoxicity and depolarization of mitochondrial membrane potential. Our studies highlight the feasibility of regulating the nanozyme activity of plasmonic nanostructures using their unique NIR plasmonic features with spatiotemporal control.

Fenton reaction-mediated oncotherapy is an emerging strategy which uses iron ions to catalytically convert endogenous hydrogen peroxide into hydroxyl radicals, the most reactive oxygen species found in biology, for efficient cancer therapy. However, Fenton reaction efficiency in tumor tissue is typically limited due to restrictive conditions. One strategy to overcome this obstacle is to increase the temperature specifically at the tumor site. Herein, a tumor-targeting iron sponge (TTIS) nanocomposite based on graphdiyne oxide, which has a high affinity for iron is described. TTIS can accumulate in tumor tissue by decoration with a tumor-targeting polymer to enable tumor photoacoustic and magnetic resonance imaging. With its excellent photothermal conversion efficiency (37.5%), TTIS is an efficient photothermal therapy (PTT) agent. Moreover, the heat produced in the process of PTT can accelerate the release of iron ions from TTIS and simultaneously enhance the efficiency of the Fenton reaction, thus achieving a combined PTT and Fenton reaction-mediated cancer therapy. This work introduces a graphdiyne oxide-based iron sponge that exerts an enhanced antitumor effect through PTT and Fenton chemistry.

Platinum (Pt)-based chemotherapy is a widely used therapeutic regimen against various cancers. However, the insufficient cellular uptake, deactivation by thiol-containing species and nonspecific distribution of cisplatin (CDDP) result in its low chemosensitivity as well as systemic side effects, which can largely constrain the employment of CDDP in clinical treatment. To circumvent these problems, in this study, polymeric nanoparticles were utilized to co-deliver a water-soluble CDDP derivative, poly (γ, L-glutamic acid)-CDDP conjugate, and a naturally occurring compound derived from broccoli, sulforaphane, which can achieve efficient glutathione (GSH) depletion, to enhance the accumulation of CDDP in cancer cells. Results show that compared with combinational treatment of CDDP and SFN, the nanoparticles were more effectively internalized and could significantly reduce GSH content in breast cancer cells, leading to a notable increase in DNA-bound Pt and DNA damage-induced apoptosis. Moreover, in an orthotopic breast cancer model, the nanoparticles achieved a significantly higher tumor accumulation and exhibited a more powerful anti-tumor activity. Finally, this nano-enhanced chemotherapy was further confirmed in a liver cancer model with high-expression of GSH. Taken together, this sulforaphane-based nano-strategy holds great promise to enhance the sensitivity and therapeutic efficacy of Pt-based chemotherapy.

Cysteine-based chiral optically active carbon dots (CDs) and their effects on cellular energy metabolism, which is vital for essential cellular functions, have been barely reported. A green and effective synthesis strategy for chiral N-S-doped CDs (fluorescence quantum yield ca. 41.26 %) based on hydrothermal treatment of l- or d-cysteine at as low as 60 °C has been developed. This suggested that cysteine was instable in aqueous solutions and acts as a warning for high-temperature synthesis of nanomaterials using cysteine as stabilizer. Human bladder cancer T24 cells treated with l-CDs showed up-regulated glycolysis, while d-CDs had no similar effects. In contrast, no disturbance to the basal mitochondrial aerobic respiration of T24 cells was caused by either chiral CD.

Safety analysis of engineered nanomaterials (ENMs) presents a formidable challenge regarding environmental health and safety, due to their complicated and diverse physicochemical properties. Although large amounts of data have been published regarding the potential hazards of these materials, we still lack a comprehensive strategy for their safety assessment, which generates a huge workload in decision-making. Thus, an integrated approach is urgently required by government, industry, academia and all others who deal with the safe implementation of nanomaterials on their way to the marketplace. The rapid emergence and sheer number of new nanomaterials with novel properties demands rapid and high-content screening (HCS), which could be performed on multiple materials to assess their safety and generate large data sets for integrated decision-making. With this approach, we have to consider reducing and replacing the commonly used rodent models, which are expensive, time-consuming, and not amenable to high-throughput screening and analysis. In this review, we present a ‘Library Integration Approach’ for high-content safety analysis relevant to the ENMs. We propose the integration of compositional and property-based ENM libraries for HCS of cells and biologically relevant organisms to be screened for mechanistic biomarkers that can be used to generate data for HCS and decision analysis. This systematic approach integrates the use of material and biological libraries, automated HCS and high-content data analysis to provide predictions about the environmental impact of large numbers of ENMs in various categories. This integrated approach also allows the safer design of ENMs, which is relevant to the implementation of nanotechnology solutions in the pharmaceutical industry.

Pancreatic cancer, one of the leading causes of cancer-related mortality, is characterized by desmoplasia and hypovascular cancerous tissue, with a 5 year survival rate of8%. To overcome the severe resistance of pancreatic cancer to conventional therapies, we synthesized gold nanoshell-coated rod-like mesoporous silica (GNRS) nanoparticles which integrated cascade tumor targeting (mediated by photothermal effect and molecular receptor binding) and photothermal treatment-enhanced gemcitabine chemotherapy, under mild near-infrared laser irradiation condition. GNRS significantly improved gemcitabine penetration and accumulation in tumor tissues, thus destroying the dense stroma barrier of pancreatic cancer and reinforcing chemosensitivity in mice. Our current findings strongly support the notion that further development of this integrated plasmonic photothermal strategy may represent a promising translational nanoformulation for effective treatment of pancreatic cancer with integral cascade tumor targeting strategy and enhanced drug delivery efficacy.

Graphdiyne has attracted much interest from researchers for their potential applications in energy storage, catalysis, and biomedical areas. As one of the derivatives of graphdiyne, graphdiyne quantum dots (GDQDs) may possess superior bioactivity due to active acetylene units. However, the biological application of biocompatible GDQDs have not been reported so far. Herein, GDQDs with uniform size and good crystallization were prepared via a classical solvothermal method. The GDQDs exhibit excitation- and pH-dependent fluorescence emission as well as superior photostability, demonstrating their potential for bioimaging. The GDQDs demonstrate efficient cellular uptake and cell imaging without induction of detectable cytotoxic effects in vitro. Systematical safety evaluation further confirmed good biocompatibility of the GDQDs in vivo. Our study preliminarily validates the application of the GDQDs in biomedicine and encourages more thorough studies for better realizing the potential of GDQDs.

Combining informative imaging methodologies with effective treatments to destroy tumors is of great importance for oncotherapy. Versatile nanotheranostic agents that inherently possess both diagnostic imaging and therapeutic capabilities are highly desirable to meet these requirements. Here, a simple but powerful nanoplatform based on polydopamine-coated gold nanostar (GNS@PDA), which can be easily diversified to achieve various function extensions, is designed to realize functional and anatomical imaging-guided photothermal oncotherapy. This nanoplatform intrinsically enables computed tomography/photoacoustic/two-photon luminescence/infrared thermal tetramodal imaging and can further incorporate fibroblast activation protein (FAP, a protease highly expressed in most of tumors) activatable near-infrared fluorescence imaging and Fe3+-based magnetic resonance imaging for comprehensive diagnosis. Moreover, GNS@PDA exhibits excellent photothermal performance and efficient tumor accumulation. Under the precise...

Rapidly growing cancer cells exhibit a strong dependence on iron for their survival. Thus, iron-removing drugs, iron chelators, have potential applications in cancer treatment. Deferoxamine (DFO) is an efficient iron chelator, but its short circulation half-life and ability to induce hypoxia-inducible factor 1α (HIF1α) overexpression restricts its use as an antitumor agent. In the present study, we first found that a pattern of iron-related protein expression favoring higher intracellular iron closely correlates with shorter overall and relapse-free survival in pancreatic cancer patients. We subsequently found that a combination of DFO and the HIF1α inhibitor, lificiguat (also named YC1), significantly enhanced the antitumor efficacy of DFO in vitro. We then employed transferrin receptor 1 (TFR1) targeting liposomes to codeliver DFO and YC1 to pancreatic tumors in a mouse model. The encapsulation of DFO prolonged its circulation time, improved its accumulation in tumor tissues via the enhanced permeability and retention (EPR) effect, and facilitated efficient uptake by cancer cells, which express high level of TFR1. After entering the tumor cells, the encapsulated DFO and YC1 were released to elicit a synergistic antitumor effect in subcutaneous and orthotopic pancreatic cancer xenografts. In summary, our work overcame two major obstacles in DFO-based cancer treatment through a simple liposome-based drug delivery system. This nanoencapsulation and targeting paradigm lays the foundation for future application of iron chelation in cancer therapy.

Photodynamic therapy (PDT) is a promising anticancer treatment and is clinically approved for different types of tumors. However, current PDT suffers several obstacles, including its neutralization by excess glutathione (GSH) in the tumor tissue and its strongly proangiogenic tumor response. In this work, a biomimic, multifunctional nanoparticle-based PDT agent, combining a tumor-targeted photosensitizer with GSH scavenging and antiangiogenesis therapy, is developed. A porphyrinic Zr-metal-organic framework nanoparticle is used simultaneously as the photosensitizer and the delivery vehicle of vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor apatinib. The core nanoparticles are wrapped in MnO2 to consume the intratumoral GSH and then decorated with a tumor cell membrane camouflage. After intravenous administration, the nanoparticles selectively accumulate in tumor through homotypic targeting mediated by the biomimic decoration, and the combination of enhanced PDT and antiangiogenic drug significantly improves their tumor inhibition efficiency. This study provides an integrated solution for mechanism-based enhancement of PDT and demonstrates the encouraging potential for multifunctional nanosystem applicable for tumor therapy.

Knowledge on the interactions between engineered nanomaterials (ENMs) and biological systems is critical both for the assessment of biological effects of ENMs and for the rational design of ENM-based products. However, probing the events that occur at the nano-bio interface remains extremely challenging due to their complex and dynamic nature. So far, the understanding of mechanisms underlying nano-bio interactions has been mainly limited by the lack of proper analytical techniques with sufficient sensitivity, selectivity and resolution for characterization of nano-bio interface events. Moreover, many classic bioanalytical methods are not suitable for direct measurement of nano-bio interface interactions. These have made establishing analytical methodologies for systematic and comprehensive study of nano-bio interface one of the most focused areas in nanobiology. In this review we have discussed some representative developments regarding analytical techniques for nano-bio interface characterization, including the improvements of traditional methods and the emergence of powerful new technologies. These developments have allowed ultrasensitive, real-time analysis of interactions between ENMs and biomolecules, transformations of ENMs in biological environment, and impacts of ENMs on living systems on molecular or cellular level.

Triple-negative breast cancer is a malignant cancer type with a high risk of early recurrence and distant metastasis. Unlike other breast cancers, triple-negative breast cancer is lack of targetable receptors and, therefore, patients largely receive systemic chemotherapy. However, inevitable adverse effects and acquired drug resistance severely constrain the therapeutic outcome. Here we tailor-designed a porphyrin-based micelle that was self-assembled from a hybrid amphiphilic polymer comprising polyethylene glycol, poly (d, l-lactide-co-glycolide) and porphyrin. The bilayer micelles can be simultaneously loaded with two chemotherapeutic drugs with synergistic cytotoxicity and distinct physiochemical properties, forming a uniform and spherical nanostructure. The drug-loaded micelles showed a tendency to accumulate in the tumor and can be internalized by tumor cells for drug release in acidic organelles. Under near-infrared laser irradiation, high density of self-quenched porphyrins in the hydrophobic layer absorbed light efficiently and converted into an excited state, leading to the release of sufficient heat for photothermal therapy. The integration of localized photothermal effect and synergistic chemotherapy conferred great chemosensitivity to cancer cells and achieved tumor regression using about 1/10 of traditional drug dosage. As a result, chemotherapy-associated adverse effects were successfully avoided. Our present study established a novel porphyrin-based nanoplatform with photothermal activity and expanded drug loading capacity, providing new opportunities for challenging conventional chemotherapy and fighting against stubborn triple-negative breast cancer.

Nanomaterial-mediated photothermal therapy has shown great potential to fulfill the unmet medical needs for treatment of tumors. In this study, a rod-like gold nanoshell capsule, which can offer both photothermal therapy and chemotherapy, is synthesized and applied for the treatment of melanoma. This nano-platform is made by developing a gold nanoshell on rod-like mesoporous silica nanoparticles with different aspect ratios, and it was found that the aspect ratio significantly influenced the cellular uptake and tumor distribution of the nanoparticles. The gold nanoshell capsules with a moderate aspect ratio are found to be efficiently taken up by melanoma cells and are able to penetrate tumor tissues, resulting in the effective ablation of highly malignant melanomas when used along with mild laser irradiation and a single treatment. This study demonstrates that the optimization of the aspect ratio is indispensable to further development of this nanoplatform for antitumor therapy. From the Clinical Editor The combination of hyperthermia and chemotherapeutic agents has been investigated as a new approach for the treatment of malignant melanoma. It appears that the aspect ratio may play an important role in the treatment efficacy. In this article, the authors studied how the AR influenced the cellular uptake and the optimal AR for antitumor effects.

Fibrotic stroma, a critical character of pancreatic tumor microenvironment, provides a critical barrier against the penetration and efficacy of various antitumor drugs. Therefore, new strategies are urgently needed to alleviate the fibrotic mass and increase the drug perfusion within pancreatic cancer tissue. In our current work, we developed a β-cyclodextrin (β-CD) modified matrix metalloproteinase-2 (MMP-2) responsive liposome, integrating antifibrosis and chemotherapeutic drugs for regulation of pancreatic stellate cells (PSCs), a key source of the fibrosis, and targeted delivery of cytotoxic drugs for pancreatic cancer therapy. These liposomes disassembed into two functional parts upon MMP-2 cleavage at the tumor site. One part was constituted by the β-CDs and the antifibrosis drug pirfenidone, which was kept in the stroma and inhibited the expression of collagen I and TGF-β in PSCs, down-regulating the fibrosis and decreasing the stromal barrier. The other segment, the RGD peptide-modified-liposome loading the chemotherapeutic drug gemcitabine, targeted and killed pancreatic tumor cells. This integrated nanomedicine, showing an increased drug perfusion without any overt side effects, may provide a potential strategy for improvement of the pancreatic cancer therapy.

Pancreatic ductal adenocarcinoma is characterised by a dense desmoplastic stroma composed of stromal cells and extracellular matrix (ECM). This barrier severely impairs drug delivery and penetration. Activated pancreatic stellate cells (PSCs) play a key role in establishing this unique pathological obstacle, but also offer a potential target for anti-tumour therapy. Here, we construct a tumour microenvironment-responsive nanosystem, based on PEGylated polyethylenimine-coated gold nanoparticles, and utilise it to co-deliver all-trans retinoic acid (ATRA, an inducer of PSC quiescence) and siRNA targeting heat shock protein 47 (HSP47, a collagen-specific molecular chaperone) to re-educate PSCs. The nanosystem simultaneously induces PSC quiescence and inhibits ECM hyperplasia, thereby promoting drug delivery to pancreatic tumours and significantly enhancing the anti-tumour efficacy of chemotherapeutics. Our combination strategy to restore homoeostatic stromal function by targeting activated PSCs represents a promising approach to improving the efficacy of chemotherapy and other therapeutic modalities in a wide range of stroma-rich tumours., Stromal-tumour interactions play an important role in pancreatic cancer progression. Here, they describe the development of a tumour microenvironment-responsive gold nanoparticle system incorporating all-trans retinoic acid (ATRA) and siRNA against heat shock protein 47 (HSP47), for use in pancreatic cancer treatment.

Photothermal-based combination therapy using functional nanomaterials shows great promise in eradication of aggressive tumors and improvement of drug sensitivity. The therapeutic efficacy and adverse effects of drug combinations depend on the precise control of timely tumor-localized drug release. Here a polymer-dopamine nanocomposite is designed for combination therapy, thermo-responsive drug release and prevention of uncontrolled drug leakage. The thermo-sensitive co-polymer poly (2-(2-methoxyethoxy) ethyl methacrylate-co-oligo (ethylene glycol) methacrylate)-co-2-(dimethylamino) ethyl methacrylate-b-poly (D, l-lactide-co-glycolide) is constructed into core-shell structured nanoparticles for co-encapsulation of two cytotoxic drugs and absorption of small interfering RNAs against survivin. The drug-loaded nanoparticles are surface-coated with polydopamine which confers the nanoformulation with photothermal activity and protects drugs from burst release. Under tumor-localized laser irradiation, polydopamine generates sufficient heat, resulting in nanoparticle collapse and instant drug release within the tumor. The combination strategy of photothermal, chemo-, and gene therapy leads to triple-negative breast cancer regression, with a decrease in the chemotherapeutic drug dosage to about 1/20 of conventional dose. This study establishes a powerful nanoplatform for precisely controlled combination therapy, with dramatic improvement of therapeutic efficacy and negligible side effects.