Cancer Modeling‐on‐a‐Chip with Future Artificial Intelligence Integration

Cancer is one of the leading causes of death worldwide, despite the large efforts to improve the understanding of cancer biology and development of treatments. The attempts to improve cancer treatment are limited by the complexity of the local milieu in which cancer cells exist. The tumor microenvironment (TME) consists of a diverse population of tumor cells and stromal cells with immune constituents, microvasculature, extracellular matrix components, and gradients of oxygen, nutrients, and growth factors. The TME is not recapitulated in traditional models used in cancer investigation, limiting the translation of preliminary findings to clinical practice. Advances in 3D cell culture, tissue engineering, and microfluidics have led to the development of “cancer‐on‐a‐chip” platforms that expand the ability to model the TME in vitro and allow for high‐throughput analysis. The advances in the development of cancer‐on‐a‐chip platforms, implications for drug development, challenges to leveraging this technology for improved cancer treatment, and future integration with artificial intelligence for improved predictive drug screening models are discussed.     

Two‐Dimensional Antimonene‐Based Photonic Nanomedicine for Cancer Theranostics

Antimonene (AM) is a recently described two‐dimensional (2D) elemental layered material. In this study, a novel photonic drug‐delivery platform based on 2D PEGylated AM nanosheets (NSs) is developed. The platform's multiple advantages include: i) excellent photothermal properties, ii) high drug‐loading capacity, iii) spatiotemporally controlled drug release triggered by near‐infrared (NIR) light and moderate acidic pH, iv) superior accumulation at tumor sites, v) deep tumor penetration by both extrinsic stimuli (i.e., NIR light) and intrinsic stimuli (i.e., pH), vi) excellent multimodal‐imaging properties, and vii) significant inhibition of tumor growth with no observable side effects and potential degradability, thus addressing several key limitations of cancer nanomedicines. The intracellular fate of the prepared NSs is also revealed for the first time, providing deep insights that improve cellular‐level understanding of the nano–bio interactions of AM‐based NSs and other emerging 2D nanomaterials. To the best of knowledge, this is the first report on 2D AM‐based photonic drug‐delivery platforms, possibly marking an exciting jumping‐off point for research into the application of 2D AM nanomaterials in cancer theranostics.     

Virion‐Like Membrane‐Breaking Nanoparticles with Tumor‐Activated Cell‐and‐Tissue Dual‐Penetration Conquer Impermeable Cancer

Poor drug penetration into tumor cells and tissues is a worldwide difficulty in cancer therapy. A strategy is developed for virion‐like membrane‐breaking nanoparticles (MBNs) to smoothly accomplish tumor‐activated cell‐and‐tissue dual‐penetration for surmounting impermeable drug‐resistant cancer. Tailor‐made dendritic arginine‐rich peptide prodrugs are designed to mimic viral protein transduction domains and globular protein architectures. Attractively, these protein mimics self‐assemble into virion‐like nanoparticles in aqueous solution, having highly ordered secondary structure. Tumor‐specific acidity conditions would activate the membrane‐breaking ability of these virion‐like nanoparticles to perforate artificial and natural membrane systems. As expected, MBNs achieve highly efficient drug penetration into drug‐resistant human ovarian (SKOV3/R) cancer cells. Most importantly, the well‐organized MBNs can pass through endothelial/tumor cells and spread from one cell to another one. Intravenous injection of MBNs into nude mice bearing impermeable SKOV3/R tumors suggests that the MBNs can recognize the tumor tissue after prolonged blood circulation, evoke the membrane‐breaking function for robust transvascular extravasation, and penetrate into the deep tumor tissue. This work provides the first demonstration of sophisticated molecular and supramolecular engineering of virion‐like MBNs to realize the long‐awaited cell‐and‐tissue dual‐penetration, contributing to the development of a brand‐new avenue for dealing with incurable cancers.     

NIR‐Responsive Polycationic Gatekeeper‐Cloaked Hetero‐Nanoparticles for Multimodal Imaging‐Guided Triple‐Combination Therapy of Cancer

Responsive multifunctional organic/inorganic nanohybrids are promising for effective and precise imaging‐guided therapy of cancer. In this work, a near‐infrared (NIR)‐triggered multifunctional nanoplatform comprising Au nanorods (Au NRs), mesoporous silica, quantum dots (QDs), and two‐armed ethanolamine‐modified poly(glycidyl methacrylate) with cyclodextrin cores (denoted as CD‐PGEA) has been successfully fabricated for multimodal imaging‐guided triple‐combination treatment of cancer. A hierarchical hetero‐structure is first constructed via integration of Au NRs with QDs through a mesoporous silica intermediate layer. The X‐ray opacity and photoacoustic (PA) property of Au NRs are utilized for tomography (CT) and PA imaging, and the imaging sensitivity is further enhanced by the fluorescent QDs. The mesoporous feature of silica allows the loading of a typical antitumor drug, doxorubicin (DOX), which are sealed by the polycationic gatekeepers, low toxic hydroxyl‐rich CD‐PGEA/pDNA complexes, realizing the co‐delivery of drug and gene. The photothermal effect of Au NRs is utilized for photothermal therapy (PTT). More interestingly, such photothermal effect also induces a cascade of NIR‐triggered release of DOX through the facilitated detachment of CD‐PGEA gatekeepers for controlled chemotherapy. The resultant chemotherapy and gene therapy for glioma tumors are complementary for the efficiency of PTT. This work presents a novel responsive multifunctional imaging‐guided therapy platform, which combines fluorescent/PA/CT imaging and gene/chemo/photothermal therapy into one nanostructure.     

Platelet Membrane‐Camouflaged Magnetic Nanoparticles for Ferroptosis‐Enhanced Cancer Immunotherapy

Although cancer immunotherapy has emerged as a tremendously promising cancer therapy method, it remains effective only for several cancers. Photoimmunotherapy (e.g., photodynamic/photothermal therapy) could synergistically enhance the immune response of immunotherapy. However, excessively generated immunogenicity will cause serious inflammatory response syndrome. Herein, biomimetic magnetic nanoparticles, Fe₃O₄‐SAS @ PLT, are reported as a novel approach to sensitize effective ferroptosis and generate mild immunogenicity, enhancing the response rate of non‐inflamed tumors for cancer immunotherapy. Fe₃O₄‐SAS@PLT are built from sulfasalazine (SAS)‐loaded mesoporous magnetic nanoparticles (Fe₃O₄) and platelet (PLT) membrane camouflage and triggered a ferroptotic cell death via inhibiting the glutamate‐cystine antiporter system X_c^? pathway. Fe₃O₄‐SAS @ PLT‐mediated ferroptosis significantly improves the efficacy of programmed cell death 1 immune checkpoint blockade therapy and achieves a continuous tumor elimination in a mouse model of 4T1 metastatic tumors. Proteomics studies reveal that Fe₃O₄‐SAS @ PLT‐mediated ferroptosis could not only induce tumor‐specific immune response but also efficiently repolarize macrophages from immunosuppressive M2 phenotype to antitumor M1 phenotype. Therefore, the concomitant of Fe₃O₄‐SAS @ PLT‐mediated ferroptosis with immunotherapy are expected to provide great potential in the clinical treatment of tumor metastasis.     

Nanoparticle‐Based Manipulation of Antigen‐Presenting Cells for Cancer Immunotherapy

Immunotherapeutic approaches for treating cancer overall have been receiving a considerable amount of interest due to the recent approval of several clinical formulations. Among the different modalities, anticancer vaccination acts by training the body to endogenously generate a response against tumor cells. However, despite the large amount of work that has gone into the development of such vaccines, the near absence of clinically approved formulations highlights the many challenges facing those working in the field. The generation of potent endogenous anticancer responses poses unique challenges due to the similarity between cancer cells and normal, healthy cells. As researchers continue to tackle the limited efficacy of vaccine formulations, fresh and novel approaches are being sought after to address many of the underlying problems. Here the application of nanoparticle technology towards the development of anticancer vaccines is discussed. Specifically, there is a focus on the benefits of using such strategies to manipulate antigen presenting cells (APCs), which are essential to the vaccination process, and how nanoparticle‐based platforms can be rationally engineered to elicit appropriate downstream immune responses.     

Two‐Dimensional Nanomaterials for Cancer Nanotheranostics

Emerging nanotechnologies show unprecedented advantages in accelerating cancer theranostics. Among them, two‐dimensional nanomaterials (2DNMs) represent a novel type of material with versatile physicochemical properties that have enabled a new horizon for applications in both cancer diagnosis and therapy. Studies have demonstrated that 2DNMs may be used in diverse aspects, including i) cancer detection due to their high propensity towards tumor markers; ii) molecular imaging for guided tumor therapies, and iii) drug and gene loading, photothermal and photodynamic cancer therapies. However, their biomedical applications raise concerns due to the limited understanding of their in vivo metabolism, transformation and possible toxicities. In this comprehensive review, the state‐of‐the‐art development of 2DNMs and their implications for cancer nanotheranostics are presented. The modification strategies to enhance the biocompatibility of 2DNMs are also reviewed.     

Breaking the Depth Dependence by Nanotechnology‐Enhanced X‐Ray‐Excited Deep Cancer Theranostics

The advancements in nanotechnology have created multifunctional nanomaterials aimed at enhancing diagnostic accuracy and treatment efficacy for cancer. However, the ability to target deep‐seated tumors remains one of the most critical challenges for certain nanomedicine applications. To this end, X‐ray‐excited theranostic techniques provide a means of overcoming the limits of light penetration and tissue attenuation. Herein, a comprehensive overview of the recent advances in nanotechnology‐enhanced X‐ray‐excited imaging and therapeutic methodologies is presented, with an emphasis on the design of multifunctional nanomaterials for contrast‐enhanced computed tomography (CT) imaging, X‐ray‐excited optical luminescence (XEOL) imaging, and X‐ray‐excited multimodal synchronous/synergistic therapy. The latter is based on the concurrent use of radiotherapy with chemotherapy, gas therapy, photodynamic therapy, or immunotherapy. Moreover, the featured biomedical applications of X‐ray‐excited deep theranostics are discussed to highlight the advantages of X‐ray in high‐sensitivity detection and efficient elimination of malignant tumors. Finally, key issues and technical challenges associated with this deep theranostic technology are identified, with the intention of advancing its translation into the clinic.