Although anti-cancer nanotherapeutics have made breakthroughs, many remain clinically unsatisfactory due to limited delivery efficiency and complicated biological barriers. Here, we prepared charge-reversible crosslinked nanoparticles (PDC NPs) by supramolecular self-assembly of pro-apoptotic peptides and photosensitizers, followed by crosslinking the self-assemblies with polyethylene glycol to impart tumor microenvironment responsiveness and charge-reversibility. The resultant PDC NPs have a high drug loading of 68.3%, substantially exceeding that of 10%–15% in conventional drug delivery systems. PDC NPs can overcome the delivery hurdles to significantly improve the tumor accumulation and endocytosis of payloads by surface charge reversal and responsive crosslinking strategy. Pro-apoptotic peptides target the mitochondrial membranes and block the respiratory effect to reduce local oxygen consumption, which extensively augments oxygen-dependent photodynamic therapy (PDT). The photosensitizers around mitochondria increased along with the peptides, allowing PDT to work with pro-apoptotic peptides synergistically to induce tumor cell death by mitochondria-dependent apoptotic pathways. Our strategy would provide a valuable reference for improving the delivery efficiency of hydrophilic peptides and developing mitochondrial-targeting cancer therapies.

Our improved knowledge of tumor immunology laid a solid foundation for the clinical use of tumor immunotherapies such as immune checkpoint blockers, and the efficacy of these drugs increased our confidence that immunomodulation was a viable way of treating cancer. The basis of immunotherapy is to break the immune escape of the tumor and resolve the immune suppressive microenvironment of tumors. Nanomaterial-mediated dynamic therapy (NDT) is an emerging immuno-regulatable type for tumor therapy, whose effects are mediated by increased cellular levels of reactive oxygen species (ROS). ROS is a potent trigger of immunogenic cell death, and this process initiates antitumor immunity. Nanomaterials for use in NDT can be engineered to interact with almost all cell types in the tumor microenvironment to remodel this environment. In this review, we systematically examined the effects of NDT on four major cell types in the tumor microenvironment, namely tumor cells, lymphocytes, myeloid cells, and tumor stromal cells. We believe that this review will improve researchers’ understanding of the anti-tumor immunity triggered by NDT, and provide ideas and inspiration for how optimally designed NDT schemes can be used to target the cells in the tumor microenvironment.

Nanoparticles-based drug delivery systems have attracted significant attention in biomedical fields because they can deliver loaded cargoes to the target site in a controlled manner. However, tremendous challenges must still be overcome to reach the expected targeting and therapeutic efficacy in vivo. These challenges mainly arise because the interaction between nanoparticles and biological systems is complex and dynamic and is influenced by the physicochemical properties of the nanoparticles and the heterogeneity of biological systems. Importantly, once the nanoparticles are injected into the blood, a protein corona will inevitably form on the surface. The protein corona creates a new biological identity which plays a vital role in mediating the bio–nano interaction and determining the ultimate results. Thus, it is essential to understand how the protein corona affects the delivery journey of nanoparticles in vivo and what we can do to exploit the protein corona for better delivery efficiency. In this review, we first summarize the fundamental impact of the protein corona on the delivery journey of nanoparticles. Next, we emphasize the strategies that have been developed for tailoring and exploiting the protein corona to improve the transportation behavior of nanoparticles in vivo. Finally, we highlight what we need to do as a next step towards better understanding and exploitation of the protein corona. We hope these insights into the “Yin and Yang” effect of the protein corona will have profound implications for understanding the role of the protein corona in a wide range of nanoparticles.

Attaching DNA/RNA to nanomaterials is the basis for nucleic acid-based assembly and drug delivery. Herein, we report that small interfering RNA (siRNA) effectively coordinates with ligand-free lanthanide nanoparticles (NaGdF₄ NPs), and forms siRNA/NaGdF₄ spherical nucleic acids (SNA). The coordination is primarily attributed to the interaction between Gd and phosphate backbone of the siRNA. Surprisingly, an efficient encapsulation and rapid endosomal escape of siRNA from the endosome/lysosome were achieved, due to its flexible ability to bound to phospholipid head of endosomal membrane, thereby disrupting the membrane structure. Resorting to the dual properties of NaGdF₄ NPs, siRNA loading, and endosomal escape, siRNA targeting programmed cell death-ligand 1 (siPD-L1)/NaGdF₄ SNA triggers significant gene silencing in vitro and in vivo, and effectively represses the tumor growth in both CT26 tumor model and 4T1 orthotopic murine model.

Vaccination is the most effective way to prevent coronavirus disease 2019 (COVID-19). Vaccine development approaches consist of viral vector vaccines, DNA vaccine, RNA vaccine, live attenuated virus, and recombinant proteins, which elicit a specific immune response. The use of nanoparticles displaying antigen is one of the alternative approaches to conventional vaccines. This is due to the fact that nano-based vaccines are stable, able to target, form images, and offer an opportunity to enhance the immune responses. The diameters of ultrafine nanoparticles are in the range of 1–100 nm. The application of nanotechnology on vaccine design provides precise fabrication of nanomaterials with desirable properties and ability to eliminate undesirable features. To be successful, nanomaterials must be uptaken into the cell, especially into the target and able to modulate cellular functions at the subcellular levels. The advantages of nano-based vaccines are the ability to protect a cargo such as RNA, DNA, protein, or synthesis substance and have enhanced stability in a broad range of pH, ambient temperatures, and humidity for long-term storage. Moreover, nano-based vaccines can be engineered to overcome biological barriers such as nonspecific distribution in order to elicit functions in antigen presenting cells. In this review, we will summarize on the developing COVID-19 vaccine strategies and how the nanotechnology can enhance antigen presentation and strong immunogenicity using advanced technology in nanocarrier to deliver antigens. The discussion about their safe, effective, and affordable vaccines to immunize against COVID-19 will be highlighted.

Bacterial outer membrane vesicle (OMV) is a kind of spherical lipid bilayer nanostructure naturally secreted by bacteria, which has diverse functions such as intracellular and extracellular communication, horizontal gene transfer, transfer of contents to host cells, and eliciting an immune response in host cells. In this review, several methods including ultracentrifugation and precipitation for isolating OMVs were summarized. The latest progresses of OMVs in biomedical fields, especially in vaccine development, cancer treatment, infection control, and bioimaging and detection were also summarized in this review. We highlighted the importance of genetic engineering for the safe and effective application and in facilitating the rapid development of OMVs. Finally, we discussed the bottleneck problems about OMVs in preparation and application at present and put forward our own suggestions about them. Some perspectives of OMVs in biomedical field were also provided.

The adaptive treatment tolerance (ATT) of cancer cells is the main encumbrance to cancer chemotherapy. A potential solution to this problem is to treat cancer cells with multiple drugs using nanoparticles (NPs). In this study, we tested the co-administration of curcumin (Cur) and doxorubicin (Dox) to MCF-7 resistant breast cancer cells to block the ATT and elicit efficient cell killing. Drugs were co-administered to cells both sequentially and simultaneously. Sequential drug co-administration was carried out by pre-treating the cells with albumin nanoparticles (ANPs) loaded with Cur (Cur@ANPs) followed by treatment with Dox-loaded ANPs (Dox@ANPs). Simultaneous drug co-administration was carried out by treating the cells with ANPs loaded with both the drugs (Cur/Dox@ANPs). We found that the simultaneous drug co-administration led to a greater intra-cellular accumulation of Dox and cell killing with respect to the sequential drug co-administration. However, the simultaneous drug co-administration led to a lower intra-cellular accumulation of Cur with respect to the sequential drug co-administration. We showed that this result was due to the aggregation and entrapment of Cur in the lysosomes as soon as it was released from Cur@ANPs, a phenomenon called lysosomotropism. In contrast, the simultaneous release of Dox and Cur from Cur/Dox@ANPs into the lysosomes led to lysosomal pH elevation, which, in turn, avoided Cur aggregation, led to lysosome swelling and drug release in the cytosol, and finally provoked efficient cell killing. Our study shed the light on the molecular processes driving the therapeutic effects of anti-cancer drugs co-administered to cancer cells in different manners.

Globally, cancer is growing at an alarming pace, which calls for development of more efficient cancer treatments. Conventional chemotherapy and radiotherapy have become crucial first-line clinical treatments for cancer. However, along with their wide usage, limited therapeutic effects, severe adverse reactions, unaffordable costs, and complicated operations lead to failures of these treatments. Moreover, the emergence of multidrug resistance inhibits the longtime usage of chemotherapeutics. One of the major causes of treatment failure is the insufficient sensitivity of cancer cells to therapeutic drugs or treatments. With the rigorous development of nanotechnology, tailored nanoparticles can efficiently sensitize malignant cells by inducing intracellular structural and functional changes, which could affect vital intracellular processes such as metabolism, signal conduction, proliferation, cell death as well as intracellular drug delivery. Here, we review recent advances in nanomaterial-assisted sensitization of oncotherapy, and challenges and strategies in the development of nanomedical approaches.

Gold nanoparticles (Au NPs) have been widely utilized in biomedical applications owing to their attractive features and biocompatibility, which greatly increase the risk of humans' being exposed to Au NPs, including pregnant women. In contrast to mature cells, embryos are more susceptible to outside disruptive stimuli. Nonetheless, a possible inhibitory effect of nanomaterials on embryonic development is usually ignored as long as the NPs do not have significant cytotoxic effects. According to our results, a minimal "nontoxic" concentration of Au NPs during early pregnancy can have lethal inhibitory effects on embryos in vivo and in vitro. We conducted important experiments on the influence of Au NPs on embryonic development and found that Au NPs can disturb embryonic development in a size- and concentration-dependent manner. Au NPs of 15 nm in diameter downregulated the expression pattern of distinct germ layer markers both at mRNA and protein levels; this action prevented differentiation of all three embryonic germ layers. Consequently, fetal resorption was observed. Our work reveals the impact of Au NPs on embryonic development and will provide an important guidance and serve as a reference for biomedical applications of Au NPs with minimal side effects.

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.