Search

Immunotherapies are now emerging as an efficient anticancer therapeutic strategy. Cancer immunotherapy utilizes the host's immune system to fight against cancer cells and has gained increasing interest due to its durable efficacy and low toxicity compared to traditional antitumor treatments, such as chemotherapy and radiotherapy (RT). Although the combination of RT and immunotherapy has drawn extensive attention in the clinical setting, the overall response rates are still low. Therefore, strategies for further improvement are urgently needed. Nanotechnology has been used in cancer immunotherapy and RT to target not only cancer cells but also the tumor microenvironment (TME), thereby helping to generate a long-term immune response. Nanomaterials can be an effective delivery system and a strong autophagy inducer, with the ability to elevate autophagy to very high levels. Interestingly, autophagy could play a critical role in optimal immune function, mediating cell-extrinsic homeostatic effects through the regulation of danger signaling in neoplastic cells under immunogenic chemotherapy and/or RT. In this review, we summarize the preclinical and clinical development of the combination of immunotherapy and RT in cancer therapy and highlight the latest progress in nanotechnology for augmenting the anticancer effects of immunotherapy and RT. The underlying mechanisms of nanomaterial-triggered autophagy in tumor cells and the TME are discussed in depth. Finally, we suggest the implications of these three strategies combined together to achieve the goal of maximizing the therapeutic advantages of cancer therapy and show recent advances in biomarkers for tumor response in the evaluation of those therapies.

Simultaneous targeting of both the tumor microenvironment and cancer cells by a single nanomedicine has not been reported to date. Here, we report the dual properties of zero-valent-iron nanoparticle (ZVI-NP) to induce cancer-specific cytotoxicity and anti-cancer immunity. Methods: Cancer-specific cytotoxicity induced by ZVI-NP was determined by MTT assay. Mitochondria functional assay, immunofluorescence staining, Western blot, RT-qPCR, and ChIP-qPCR assays were used to dissect the mechanism underlying ZVI-NP-induced ferroptotic cancer cell death. The therapeutic potential of ZVI-NP was evaluated in immunocompetent mice and humanized mice. Immune cell profiles of allografts and ex vivo cultured immune cells were examined by flow cytometry analysis, RT-qPCR assay, and immunofluorescence. Results: ZVI-NP caused mitochondria dysfunction, intracellular oxidative stress, and lipid peroxidation, leading to ferroptotic death of lung cancer cells. Degradation of NRF2 by GSK3/β-TrCP through AMPK/mTOR activation was enhanced in such cancer-specific ferroptosis. In addition, ZVI-NP attenuated self-renewal ability of cancer and downregulated angiogenesis-related genes. Importantly, ZVI-NP augmented anti-tumor immunity by shifting pro-tumor M2 macrophages to anti-tumor M1, decreasing the population of regulatory T cells, downregulating PD-1 and CTLA4 in CD8+ T cells to potentiate their cytolytic activity against cancer cells, while attenuating PD-L1 expression in cancer cells in vitro and in tumor-bearing immunocompetent mice. In particular, ZVI-NPs preferentially accumulated in tumor and lung tissues, leading to prominent suppression of tumor growth and metastasis. Conclusions: This dual-functional nanomedicine established an effective strategy to synergistically induce ferroptotic cancer cell death and reprogram the immunosuppressive microenvironment, which highlights the potential of ZVI-NP as an advanced integrated anti-cancer strategy.

The development of optical organic nanoparticles (NPs) is desirable and widely studied. However, most organic chromophores are water-insoluble, and therefore, the derivatization and modification of these chromophores are difficult. Herein, we demonstrated a simple platform for the fabrication of organic nanoemitters by loading ten different organic dyes (molar masses of 479.1-1081.7 g/mol) into water-soluble polymer nanosponges composed of poly(styrene-alt-maleic acid) (PSMA). This nanolization strategy enables the incorporation of small commercial dyes (3.7–50% loading) and newly synthesized large photosensitive molecules (> 85% loading) into PSMA NPs and prevents the spontaneous aggregation of these hydrophobic chromophores in aqueous solutions. These low-cytotoxicity organic nanoparticles exhibited tunable red to near-infrared fluorescence emission for cellular imaging and biological tracking in vivo. Moreover, PSMA NPs loaded with designed NIR-photosensitive molecules were fabricated, and photodynamic therapy with these dye-loaded PSMA NPs for the photolysis of cancer cells was achieved when coupled with 808 nm laser excitation. Indeed, our work demonstrates a facile approach for increasing the biocompatibility and stability of organic dyes by loading them into water-soluble polymer-based carriers, providing a new perspective of organic optoelectronic materials in biomedical theranostic applications.

Nanotechnology has rapidly promoted the development of a new generation of industrial and commercial products; however, it has also raised some concerns about human health and safety. To evaluate the toxicity of the great diversity of nanomaterials (NMs) in the traditional manner, a tremendous number of safety assessments and a very large number of animals would be required. For this reason, it is necessary to consider the use of alternative testing strategies or methods that reduce, refine, or replace (3Rs) the use of animals for assessing the toxicity of NMs. Autophagy is considered an early indicator of NM interactions with cells and has been recently recognized as an important form of cell death in nanoparticle-induced toxicity. Impairment of autophagy is related to the accelerated pathogenesis of diseases. By using mechanism-based high-throughput screening in vitro, we can predict the NMs that may lead to the generation of disease outcomes in vivo. Thus, a tiered testing strategy is suggested that includes a set of standardized assays in relevant human cell lines followed by critical validation studies carried out in animals or whole organism models such as C. elegans (Caenorhabditis elegans), zebrafish (Danio rerio), and Drosophila (Drosophila melanogaster)for improved screening of NM safety. A thorough understanding of the mechanisms by which NMs perturb biological systems, including autophagy induction, is critical for a more comprehensive elucidation of nanotoxicity. A more profound understanding of toxicity mechanisms will also facilitate the development of prevention and intervention policies against adverse outcomes induced by NMs. The development of a tiered testing strategy for NM hazard assessment not only promotes a more widespread adoption of non-rodent or 3R principles but also makes nanotoxicology testing more ethical, relevant, and cost- and time-efficient.

An iron oxide (Fe3O4)-mediated photothermal treatment has been revealed as the next generation of noninvasive and nontoxic theranostic nanoagents compared with other inorganic nanoparticles. Nevertheless, iron oxide with NIR-mediated activity is limited by its inability to be mass produced and its long-lasting photon-to-thermal conversion. Herein, we develop using a green reagent, tannic acid (TNA), which assisted hydrothermal reaction to generate black Fe3O4 nanoparticles by using commercially available nanoptical γ-Fe2O3 NPs as a starting material. The phase transformation from γ-Fe2O3 to the reduced form of Fe3O4 is assisted by TNA in the solution phase. Based on the formation of the interfacial TNA-Fe chelation and the delicate phase transformation from γ-Fe2O3 to Fe3O4 structures, the colloidal black Fe3O4 nanoparticles exhibit broad absorption that covers the visible and NIR wavelengths. Specific interfacial ligand-to-metal charge transfers between the TNA and iron ions at the surface of iron oxide nanoparticles, improves the absorbance and leads to the highest photon-to-thermal conversion (η = 35.7%) at 808 nm compared with other iron oxide nanomaterials. After modifying d-mannose (MA) onto the surface of the Fe3O4@TNA nanoparticles, the local heat can efficiently transfer from the Fe3O4@TNA nanoparticles to the vicinity of the bacterial FimH adhesion molecule, causing extensive photothermal injury to O157:H7 and ESBL strain bacteria with over 99% cell death at 200 ppm[Fe] with 808 nm light at 2.25 mW/cm2. Based on its robust photostability, Fe3O4@TNA@MA shows photothermal bactericidal recyclability through magnetic collection, adhesion, and photothermal processes.

Infection patterns of parasites, including their prevalence, diversity and host specificity, can be impacted by many biological and environmental factors, but no study has focused on the circadian rhythms of vertebrate hosts, which may affect susceptibilities and encounter rates between hosts and vectors and further shape host-parasite associations. In this study, we focused on avian haemosporidians, a classical model in studies of host-parasite associations, and investigated the infection patterns in rescued raptors brought to the Beijing Raptor Rescue Center during 2007–2020. We first assessed the association between prevalence and host biotic traits, haemosporidian prevalence was higher in the nocturnal raptors than in the diurnal raptors, and the prevalence of Haemoproteus and Leucocytozoon in the nocturnal raptors was significantly higher than that in the diurnal raptors. Furthermore, we analysed the phylogenetic relationship and host-parasite network-level differences of haemosporidian parasites in diurnal and nocturnal raptors, and demonstrated that the lineages infecting the diurnal and nocturnal raptors were not clearly separated, but the nocturnal lifestyle led to a more specialized host-parasite network structure. These variations in host-parasite associations may be driven by different susceptibilities of the hosts and the diversity or abundance of vectors during the day and night. Our study provides new insight into host-parasite associations shaped by circadian rhythm and calls for more studies on the underlying mechanisms of parasite infection.

Although inorganic silver-based nanoparticles (NPs) have been used to replace antibiotics to treat environmental microorganisms, the silver ion diffusion mechanism takes at least hours to poison the bacteria and cannot destruct the bacteria immediately. In this paper, we developed a concise oxidation process of heterostructured Ag@AuAg hollow NPs in a H2O2/PBS solution to generate AgCl nanocrystals and high-oxidation-state (hos) metal species. The hos/AgCl-assembled NPs offered a strong redox reaction to kill bacteria at 1.25 ppm[Ag] which was lower minimal inhibition concentration value than the utility of Ag ions and Ag NPs. A rapid meet-dip-kill process to disintegrate the bacterial membrane was observed within 60 min. The continuous release of Ag ions from AgCl blocks served as a smart bactericide to sustainably inhibit bacterial growth up to 7 days. The hos/AgCl-based bactericide induced enhanced evolution of a distinctive subpopulation with rigid membrane structure against both Ag ions and Ag-based NPs. This Ag-resistant persister behaved the downregulation of energy consumption and the physical insulation for Ag ions by secreting bio-reductants to convert Ag ions to less toxic Ag NPs. Based on our findings, hos/AgCl-assembled NPs endowed multiple antibacterial effects with no prominent findings of toxicity in the liver and kidneys, which opens a new era to understand the antimicrobial mechanism and resistant risk of Ag-related NPs for future clinical and environmental application.

Clinical management of Clostridium difficile infection is still far from satisfactory as bacterial spores are resistant to many chemical agents and physical treatments. Certain types of nanoparticles have been demonstrated to exhibit anti-microbial efficacy even in multi-drug resistance bacteria. However, most of these studies failed to show biocompatibility to the mammalian host cells and no study has revealed in vivo efficacy in C. difficile infection animal models. The spores treated with 500 µg/mL Fe3-δO4 nanoparticles for 20 minutes, 64% of the spores were inhibited from transforming into vegetative cells, which was close to the results of the sodium hypochlorite-treated positive control. By cryo-electron micro-tomography, we demonstrated that Fe3-δO4 nanoparticles bind on spore surfaces and reduce the dipicolinic acid (DPA) released by the spores. In a C. difficile infection animal model, the inflammatory level triple decreased in mice with colonic C. difficile spores treated with Fe3-δO4 nanoparticles. Histopathological analysis showed a decreased intense neutrophil accumulation in the colon tissue of the Fe3-δO4 nanoparticle-treated mice. Fe3-δO4 nanoparticles, which had no influence on gut microbiota and apparent side effects in vivo, were efficacious inhibitors of C. difficile spore germination by attacking its surface and might become clinically feasible for prophylaxis and therapy.

To evaluate the iron ion release profile of zero-valent iron (ZVI)-based nanoparticles (NPs) and their relationship with lysosomes in cancer cells, silica and mesoporous silica-coated ZVI NPs (denoted as ZVI@SiO2 and ZVI@mSiO2) were synthesized and characterized for the following study of cytotoxicity, intracellular iron ion release, and their underlying mechanisms. ZVI@mSiO2 NPs showed higher cytotoxicity than ZVI@SiO2 NPs in the OEC-M1 oral cancer cell line. In addition, internalized ZVI@mSiO2 NPs deformed into hollow and void structures within the cells after a 24-h treatment, but ZVI@SiO2 NPs remained intact after internalization. The intracellular iron ion release profile was also accordant with the structural deformation of ZVI@mSiO2 NPs. Burst iron ion release occurred in ZVI@mSiO2-treated cells within an hour with increased lysosome membrane permeability, which induced massive reactive oxygen species generation followed by necrotic and apoptotic cell death. Furthermore, inhibition of endosome&ndash, lysosome system acidification successfully compromised burst iron ion release, thereby reversing the cell fate. An in vivo test also showed a promising anticancer effect of ZVI@mSiO2 NPs without significant weight loss. In conclusion, we demonstrated the anticancer property of ZVI@mSiO2 NPs as well as the iron ion release profile in time course within cells, which is highly associated with the surface coating of ZVI NPs and lysosomal acidification.

Finding a cancer-selective drug that avoids damaging healthy cells and organs is a holy grail in medical research. In our previous studies, gold-coated iron (Fe@Au) nanoparticles showed cancer selective anti-cancer properties in vitro and in vivo but were found to gradually lose that activity with storage or “ageing„. To determine the reasons for this diminished anti-cancer activity, we examined Fe@Au nanoparticles at different preparation and storage stages by means of transmission electron microscopy combined with and energy-dispersive X-ray spectroscopy, along with X-ray diffraction analysis and cell viability tests. We found that dried and reconstituted Fe@Au nanoparticles, or Fe@Au nanoparticles within cells, decompose into irregular fragments of γ-F2O3 and agglomerated gold clumps. These changes cause the loss of the particles’ anti-cancer effects. However, we identified that the anti-cancer properties of Fe@Au nanoparticles can be well preserved under argon or, better still, liquid nitrogen storage for six months and at least one year, respectively.