Monodisperse and Uniform Mesoporous Silicate Nanosensitizers Achieve Low‐Dose X‐Ray‐Induced Deep‐Penetrating Photodynamic Therapy

X‐ray‐induced photodynamic therapy (X‐PDT) combines both the advantages of radiotherapy (RT) and PDT, and has considerable potential applications in clinical deep‐penetrating cancer therapy. However, it is still a major challenge to prepare monodisperse nanoscintillators with uniform size and high light yield. In this study, a general and rapid synthesis method is presented that can achieve large‐scale preparation of monodisperse and uniform silicate nanoscintillators. By simply adjusting the metal dopants, silicate nanoscintillators with controllable size and X‐ray‐excited optical luminescence (450–900 nm) are synthesized by employing a general ion‐incorporated silica‐templating method. To make full use of external radiation, the silicate nanoscintillators are conjugated with photosensitizer rose bengal and arginylglycylaspartic acid (RGD) peptide, making them intrinsically dual‐modal targeted imaging probes. Both in vitro and in vivo experiments demonstrate that the silicate nanosensitizers can accumulate effectively in tumors and achieve significant inhibitory effect on tumor progression under low‐dose X‐ray irradiation, while minimally affecting normal tissues. The insights gained in this study may provide an attractive route to synthesize nanosensitizers to overcome some of the limitations of RT and PDT in cancer treatment.     

Multifunctional Mesoporous Silica Nanoparticles with Thermal‐Responsive Gatekeeper for NIR Light‐Triggered Chemo/Photothermal‐Therapy

In this work, a matrix metalloproteinase (MMP)‐triggered tumor targeted mesoporous silica nanoparticle (MSN) is designed to realize near‐infrared (NIR) photothermal‐responsive drug release and combined chemo/photothermal tumor therapy. Indocyanine green (ICG) and doxorubicin (DOX) are both loaded in the MSN modified with thermal‐cleavable gatekeeper (Azo‐CD), which can be decapped by ICG‐generated hyperthermia under NIR illumination. A peptidic sequence containing a short PEG chain, matrix metalloproteinase (MMP) substrate (PLGVR) and tumor cell targeting motif (RGD) are further decorated on the MSN via a host–guest interaction. The PEG chain can protect the MSN during the circulation and be cleaved off in the tumor tissues with overexpressed MMP, and then the RGD motif is switched on to target tumor cells. After the tumor‐triggered targeting process, the NIR irradiation guided by ICG fluorescence can trigger cytosol drug release and realize combined chemo/photothermal therapy.     

Biocompatibility,Biodistribution, and Drug‐Delivery Efficiency of Mesoporous Silica Nanoparticles for Cancer Therapy in Animals

Mesoporous silica nanoparticles (MSNs) are a promising material for drug delivery. In this Full Paper, MSNs are first shown to be well tolerated, as demonstrated by serological, hematological, and histopathological examinations of blood samples and mouse tissues after MSN injection. Biodistribution studies using human cancer xenografts are carried out with in vivo imaging and fluorescent microscopy imaging, as well as with inductively coupled plasma mass spectroscopy. The results show that MSNs preferentially accumulate in tumors. Finally, the drug‐delivery capability of MSNs is demonstrated by following tumor growth in mice treated with camptothecin‐loaded MSNs. These results indicate that MSNs are biocompatible, preferentially accumulate in tumors, and effectively deliver drugs to the tumors and suppress tumor growth.     

The Architecture and Function of Monoclonal Antibody‐Functionalized Mesoporous Silica Nanoparticles Loaded with Mifepristone: Repurposing Abortifacient for Cancer Metastatic Chemoprevention

The circulating tumor cells (CTCs) existing in cancer survivors are considered the root cause of cancer metastasis. To prevent the devastating metastasis cascade from initiation, we hypothesize that a biodegradable nanomaterial loaded with the abortifacient mifepristone (MIF) and conjugated with the epithelial cell adhesion molecule antibody (aEpCAM) may serve as a safe and effective cancer metastatic preventive agent by targeting CTCs and preventing their adhesion‐invasion to vascular intima. It is demonstrated that MIF‐loaded mesoporous silica nanoparticles (MSN) coated with aEpCAM (aE‐MSN‐M) can specifically target and bind colorectal cancer cells in either cell medium or blood through EpCAM recognition proven by quantitative flow cytometric detection and free aEpCAM competitive assay. The specific binding results in downregulation of the captured cells and drives them into G0/G1 phase primarily attributed to the effect of aEpCAM. The functional nanoparticles significantly inhibit the heteroadhesion between cancer cells and endothelial cells, suggesting the combined inhibition effects of aEpCAM and MIF on E‐selectin and ICAM‐1 expression. The functionalized nanoparticles circulate in mouse blood long enough to deliver MIF and inhibit lung metastasis. The present proof‐of‐concept study shows that the aE‐MSN‐M can prevent cancer metastasis by restraining CTC activity and their adhesion‐invasion to vascular intima.     

Development of Dual‐Pore Coexisting Branched Silica Nanoparticles for Efficient Gene–Chemo Cancer Therapy

Various strategies for combination therapy to overcome current limitations in cancer therapy have been actively investigated. Among them, simultaneous delivery of multiple drugs is a subject of high interest due to anticipated synergistic effect, but there have been difficulties in designing and developing effective nanomaterials for this purpose. In this work, dual‐pore coexisting hybrid porous silica nanoparticles are developed through Volmer–Weber growth pathway for efficient co‐delivery of gene and anticancer drug. Based on the different pore sizes (2–3 and 40–45 nm) and surface modifications of the core and branch domains, loading and controlled release of gene and drug are achieved by appropriate strategies for each environment. With excellent loading capacity and low cytotoxicity of the present platform, the combinational cancer therapy is successfully demonstrated against human cervical cancer cell line. Through a series of quantitative analyses, the excellent gene–chemo combinational therapeutic efficiency is successfully demonstrated. It is expected that the present nanoparticle will be applicable to various biomedical fields that require co‐delivery of small molecule and nucleic acid.     

Metalloporphyrin Complex‐Based Nanosonosensitizers for Deep‐Tissue Tumor Theranostics by Noninvasive Sonodynamic Therapy

Metal complexes are widely used as anticancer drugs, while the severe side effects of traditional chemotherapy require new therapeutic modalities. Sonodynamic therapy (SDT) provides a significantly noninvasive ultrasound (US) treatment approach by activating sonosensitizers and initiating reactive oxygen species (ROS) to damage malignant tissues. In this work, three metal 4‐methylphenylporphyrin (TTP) complexes (MnTTP, ZnTTP, and TiOTTP) are synthesized and encapsulated with human serum albumin (HSA) to form novel nanosonosensitizers. These nanosonosensitizers generate abundant singlet oxygen (¹O₂) under US irradiation, and importantly show excellent US‐activatable abilities with deep‐tissue depths up to 11 cm. Compared to ZnTTP‐HSA and TiOTTP‐HSA, MnTTP‐HSA exhibits the strongest ROS‐activatable behavior due to the lowest highest occupied molecular orbital?lowest unoccupied molecular orbital gap energy by density functional theory. It is also effective for deep‐tissue photoacoustic/magnetic resonance dual‐modal imaging to trace the accumulation of nanoparticles in tumors. Moreover, MnTTP‐HSA intriguingly achieves high SDT efficiency for simultaneously suppressing the growth of bilateral tumors away from ultrasound source in mice. This work develops a deep‐tissue imaging‐guided SDT strategy through well‐defined metalloporphyrin nanocomplexes and paves a new way for highly efficient noninvasive SDT treatments of malignant tumors.     

Core‐Cone Structured Monodispersed Mesoporous Silica Nanoparticles with Ultra‐large Cavity for Protein Delivery

A new type of monodispersed mesoporous silica nanoparticles with a core–cone structure (MSN‐CC) has been synthesized. The large cone‐shaped pores are formed by silica lamellae closely packed encircling a spherical core, showing a structure similar to the flower dahlia. MSN‐CC has a large pore size of 45 nm and a high pore volume of 2.59 cm³ g⁻¹. MSN‐CC demonstrates a high loading capacity of large proteins and successfully delivers active β‐galactosidase into cells, showing their potential as efficient nanocarriers for the cellular delivery of proteins with large molecular weights.     

Fe–Au Nanoparticle‐Coupling for Ultrasensitive Detections of Circulating Tumor DNA

Effectiveness of cancer therapy relies heavily on the efficient early diagnosis. Circulating tumor DNA (ctDNA) detection is one of the most clinically meaningful liquid biopsy approaches for the noninvasive cancer early diagnosis, which, unfortunately, cannot be applied as a routine diagnostic tool till a number of obstacles, for example, unsatisfactory specificity and sensitivity, and extremely high costs, are overcome. Here, the first paradigm of nanomaterial's application in the extremely specific, ultrasensitive, and yet economical ctDNA detections is reported based on a facile nanoparticle‐coupling strategy without amplification, with which polymerase chain reaction (PCR)‐introduced bias and other shortcomings are successfully circumvented. Aiming at seven Kirsten rat sarcoma‐2 virus (KRAS) point mutations, the present strategy exhibits high specificity and an ultrahigh sensitivity of detecting as low as 0.1 pg mL^?1 of KRAS point mutation without prior PCR amplification. Discriminating KRAS gene mutations in lung adenocarcinoma patients at an extremely low detection limit equivalent to 0.12% mutation relative to wild‐type gene is successful. It is envisioned that this nanoparticle‐coupling approach could be routinely applied clinically for ultra‐early diagnosis and monitoring of diverse malignant tumors, thus facilitating the fight against cancer.     

Responsive Assembly of Upconversion Nanoparticles for pH‐Activated and Near‐Infrared‐Triggered Photodynamic Therapy of Deep Tumors

Upconversion nanoparticle (UCNP)‐mediated photodynamic therapy has shown great effectiveness in increasing the tissue‐penetration depth of light to combat deep‐seated tumors. However, the inevitable phototoxicity to normal tissues resulting from the lack of tumor selectivity remains as a major challenge. Here, the development of tumor‐pH‐sensitive photodynamic nanoagents (PPNs) comprised of self‐assembled photosensitizers grafted pH‐responsive polymeric ligands and UCNPs is reported. Under neutral pH conditions, photosensitizers aggregated in the PPNs are self‐quenched; however, upon entry into a tumor microenvironment with lower pH, the PPNs not only exhibit enhanced tumor‐cell internalization due to charge reversal but also are further disassembled into well‐dispersed nanoparticles in the endo/lysosomes of tumor cells, enabling the efficient activation of photosensitizers. The results demonstrate the attractive properties of both UCNP‐mediated deep‐tissue penetration of light and high therapeutic selectivity in vitro and in vivo.     

Safe and Effective Reversal of Cancer Multidrug Resistance Using Sericin‐Coated Mesoporous Silica Nanoparticles for Lysosome‐Targeting Delivery in Mice

Multidrug resistance (MDR) and adverse side effects are the major challenges facing cancer chemotherapy. Here, pH/protease dually responsive, sericin‐coated mesoporous silica nanoparticles (SMSNs) for lysosomal delivery of doxorubicin (DOX) to overcome MDR and reduce systemic toxicity are reported. Sericin, a natural protein from silkworm cocoons, is coated onto MSNs as a gatekeeper via pH sensitive imine linkages. The sericin shell prevents the premature leakage of encapsulated DOX from MSNs in extracellular environment. Once reaching drug‐resistant tumors, sericin's cell‐adhesive bioactivity enhances cellular uptake of SMSNs that are in turn transported into perinuclear lysosomes, thus avoiding drug efflux mediated by membrane‐bound pumps. Lysosomal acidity triggers cleavage of pH sensitive linkage between sericin and MSNs concurrently with lysosomal proteases deconstructing sericin shell. This pH/protease dual responsiveness leads to DOX burst release into cell nuclei, inducing effective cell death, thus reversing MDR. These DOX‐loaded SMSNs not only effectively kill drug‐resistant cells in vitro, but also significantly reduce the growth of DOX‐resistant MCF‐7/ADR (breast cancer cells) tumor by 70% in a preclinical animal model without eliciting systemic toxicity frequently encountered in current clinical therapeutic formulations. Thus, the dually responsive SMSNs are an effective, lysosome‐tropic, and bio‐safe delivery system for chemotherapeutics for combating MDR.     

ROS‐Responsive Polyprodrug Nanoparticles for Triggered Drug Delivery and Effective Cancer Therapy

The application of nanoparticles (NPs) to drug delivery has led to the development of novel nanotherapeutics for the treatment of various diseases including cancer. However, clinical use of NP‐mediated drug delivery has not always translated into improved survival of cancer patients, in part due to the suboptimal properties of NP platforms, such as premature drug leakage during preparation, storage, or blood circulation, lack of active targeting to tumor tissue and cells, and poor tissue penetration. Herein, an innovative reactive oxygen species (ROS)‐responsive polyprodrug is reported that can self‐assemble into stable NPs with high drug loading. This new NP platform is composed of the following key components: (i) polyprodrug inner core that can respond to ROS for triggered release of intact therapeutic molecules, (ii) polyethylene glycol (PEG) outer shell to prolong blood circulation; and (iii) surface‐encoded internalizing RGD (iRGD) to enhance tumor targeting and tissue penetration. These targeted ROS‐responsive polyprodrug NPs show significant inhibition of tumor cell growth both in vitro and in vivo.     

Single‐Particle Cryo‐EM and 3D Reconstruction of Hybrid Nanoparticles with Electron‐Dense Components

Single‐particle cryo‐electron microscopy (cryo‐EM), accompanied with 3D reconstruction, is a broadly applicable tool for the structural characterization of macromolecules and nanoparticles. Recently, the cryo‐EM field has pushed the limits of this technique to higher resolutions and samples of smaller molecular mass, however, some samples still present hurdles to this technique. Hybrid particles with electron‐dense components, which have been studied using single‐particle cryo‐EM yet with limited success in 3D reconstruction due to the interference caused by electron‐dense elements, constitute one group of such challenging samples. To process such hybrid particles, a masking method is developed in this work to adaptively remove pixels arising from electron‐dense portions in individual projection images while maintaining maximal biomass signals for subsequent 2D alignment, 3D reconstruction, and iterative refinements. As demonstrated by the success in 3D reconstruction of an octahedron DNA/gold hybrid particle, which has been previously published without a 3D reconstruction, the devised strategy that combines adaptive masking and standard single‐particle 3D reconstruction approach has overcome the hurdle of electron‐dense elements interference, and is generally applicable to cryo‐EM structural characterization of most, if not all, hybrid nanomaterials with electron‐dense components.