A Pioglitazone Nanoformulation Designed for Cancer-Associated Fibroblast Reprogramming and Cancer Treatment.

The recent focus of cancer therapeutics research revolves around modulating the immunosuppressive tumor microenvironment (TME) to enhance efficacy. The tumor stroma, primarily composed of cancer-associated fibroblasts (CAFs), poses significant obstacles to therapeutic penetration, influencing resistance and tumor progression. Reprogramming CAFs into an inactivated state has emerged as a promising strategy, necessitating innovative approaches. This study pioneers the design of a nanoformulation using pioglitazone, a Food and Drug Administration-approved anti-diabetic drug, to reprogram CAFs in the breast cancer TME. Glutathione (GSH)-responsive dendritic mesoporous organosilica nanoparticles loaded with pioglitazone (DMON-P) are designed for the delivery of cargo to the GSH-rich cytosol of CAFs. DMON-P facilitates pioglitazone-mediated CAF reprogramming, enhancing the penetration of doxorubicin (Dox), a therapeutic drug. Treatment with DMON-P results in the downregulation of CAF biomarkers and inhibits tumor growth through the effective delivery of Dox. This innovative approach holds promise as an alternative strategy for enhancing therapeutic outcomes in CAF-abundant tumors, particularly in breast cancer.

Mesoporous silica/organosilica nanoparticles for cancer immunotherapy.

Cancer is one of the fatal diseases in the history of humankind. In this regard, cancer immunotherapeutic strategies have revolutionized the traditional mode of cancer treatment. Silica based nano-platforms have been extensively applied in nanomedicine including cancer immunotherapy. Mesoporous silica nanoparticles (MSN) and mesoporous organosilica nanoparticles (MON) are attractive candidates due to the ease in controlling the structural parameters as needed for the targeted immunotherapeutic applications. Especially, the MON provide an additional advantage of controlling the composition and modulating the biological functions to actively synergize with other immunotherapeutic strategies. In this review, the applications of MSN, MON, and metal-doped MSN/MON in the field of cancer immunotherapy and tumor microenvironment regulation are comprehensively summarized by highlighting the structural and compositional attributes of the silica-based nanoplatforms.

Mesoporous sodium four-coordinate aluminosilicate nanoparticles modulate dendritic cell pyroptosis and activate innate and adaptive immunity.

Pyroptosis is a programmed cell death widely studied in cancer cells for tumour inhibition, but rarely in dendritic cell (DC) activation for vaccine development. Here, we report the synthesis of sodium stabilized mesoporous aluminosilicate nanoparticles as DC pyroptosis modulators and antigen carriers. By surface modification of sodium-stabilized four-coordinate aluminium species on dendritic mesoporous silica nanoparticles, the resultant Na-IVAl-DMSN significantly activated DC through caspase-1 dependent pyroptosis via pH responsive intracellular ion exchange. The released proinflammatory cellular contents further mediated DC hyperactivation with prolonged cytokine release. In vivo studies showed that Na-IVAl-DMSN induced enhanced cellular immunity mediated by natural killer (NK) cells, cytotoxic T cells, and memory T cells as well as humoral immune response. Our results provide a new principle for the design of next-generation nanoadjuvants for vaccine applications.

Surface chemistry of spiky silica nanoparticles tailors polyethyleneimine binding and intracellular DNA delivery.

Cellular delivery of DNA using silica nanoparticles has attracted great attention. Typically, polyethyleneimine (PEI) is used to form a silica/PEI composite vector. Understanding the interactions at the silica and PEI interface is important for successful DNA delivery and transfection, especially for silica with different surface functionality. Herein, we report that a higher content of hydrogen boning formed between PEI molecules and phosphonate modified silica nanoparticles could slow down the PEI dissolution from the freeze-dried solid composites into aqueous solution than the bare silica counterpart. The pronounced PEI retention ability through phosphonation of silica nanoparticles effectively improves the transfection efficiency due to the high DNA binding affinity extracellularly, effective lysosome escape and high nuclear entry of both PEI and DNA intracellularly. Our study provides a fundamental understanding on designing effective silica-PEI-based nano-vectors for DNA delivery applications.

Nanostructured Organosilica Nitric Oxide Donors Intrinsically Regulate Macrophage Polarization with Antitumor Effect.

Nitric oxide (NO) has many important biological functions; however, it has been a long-standing challenge to utilize the exogenous NO donor itself in the activation of macrophages for cancer immunotherapy. Herein, we report the synthesis of a nanoparticle-based NO delivery platform with a rational design for effective NO delivery and macrophage activation. S-Nitrosothiol (SNO) modified organosilica nanoparticles with a tetrasulfide-containing composition produced a higher level of intracellular NO than their bare silica counterparts in macrophages. Enhanced intracellular delivery of NO resulted in mitochondrial dysfunction and disruption of the tricarboxylic acid cycle, leading to macrophage activation and delayed tumor growth. This study provides insights on intracellularly delivered NO for regulating the polarization of macrophages and cancer immunotherapy.

Nanochemistry Modulates Intracellular Decomposition Routes of S-Nitrosothiol Modified Silica-Based Nanoparticles.

Cellular delivery of nitric oxide (NO) using NO donor moieties such as S-nitrosothiol (SNO) is of great interest for various applications. However, understandings of the intracellular decomposition routes of SNO toward either NO or ammonia (NH3 ) production are surprisingly scarce. Herein, the first report of SNO modified mesoporous organosilica nanoparticles with tetrasulfide bonds for enhanced intracellular NO delivery, ≈10 times higher than a commercial NO donor, is presented. The tetrasulfide chemistry modulates the SNO decomposition by shifting from NH3 to NO production in glutathione rich cancer cells. This study provides a new strategy to control the NO level in biological systems.

Openwork@Dendritic Mesoporous Silica Nanoparticles for Lactate Depletion and Tumor Microenvironment Regulation.

The direct depletion of lactate accumulated in the tumor microenvironment holds promise for cancer therapy but remains challenging. Herein, we report a one-pot synthesis of openwork@ dendritic mesoporous silica nanoparticles (ODMSNs) to address this problem. ODMSNs self-assembled through a time-resolved lamellar growth mechanism feature an openworked core and a dendritic shell, both constructed by silica nanosheets of ≈3 nm. With a large pore size, high surface area and pore volume, ODMSNs exhibited a high loading capacity (>0.7 g g-1 ) of lactate oxidase (LOX) and enabled intratumoral lactate depletion by >99.9 %, leading to anti-angiogenesis, down-regulation of vascular endothelial growth factor, and increased tumor hypoxia. The latter event facilitates the activation of a co-delivered prodrug for enhancing anti-tumor and anti-metastasis efficacy. This study provides an innovative nano-delivery system and demonstrates the first example of direct lactate-depletion-enabled chemotherapy.

Post translational modification-assisted cancer immunotherapy for effective breast cancer treatment.

Post translational modifications (PTM) such as phosphorylation are often correlated with tumorigenesis and malignancy in breast cancer. Herein, we report a PTM-assisted strategy as a simplified version of a personalized cancer vaccine for enhanced cancer immunotherapy. Titanium modified dendritic mesoporous silica nanoparticles (TiDMSN) are applied to assist the specific enrichment of phosphorylated tumor antigens released upon immunogenic cell death. This strategy significantly improved the tumor inhibition efficacy in a bilateral breast cancer model and the expansion of both CD8+ and CD4+ T cells in the distant tumor site. The nanotechnology based PTM-assisted strategy provides a simple and generalizable methodology for effective personalized cancer immunotherapy.

Crystal Structure of Faradaurate-279: Au279(SPh-tBu)84 Plasmonic Nanocrystal Molecules.

We report the discovery of an unprecedentedly large, 2.2 nm diameter, thiolate protected gold nanocrystal characterized by single crystal X-ray crystallography (sc-XRD), Au279(SPh-tBu)84 named Faradaurate-279 (F-279) in honor of Michael Faraday's (1857) pioneering work on nanoparticles. F-279 nanocrystal has a core-shell structure containing a truncated octahedral core with bulk face-centered cubic-like arrangement, yet a nanomolecule with a precise number of metal atoms and thiolate ligands. The Au279S84 geometry was established from a low-temperature 120 K sc-XRD study at 0.90 Å resolution. The atom counts in core-shell structure of Au279 follows the mathematical formula for magic number shells: Au@Au12@Au42@Au92@Au54, which is further protected by a final shell of Au48. Au249 core is protected by three types of staple motifs, namely: 30 bridging, 18 monomeric, and 6 dimeric staple motifs. Despite the presence of such diverse staple motifs, Au279S84 structure has a chiral pseudo-D3 symmetry. The core-shell structure can be viewed as nested, concentric polyhedra, containing a total of five forms of Archimedean solids. A comparison between the Au279 and Au309 cuboctahedral superatom model in shell-wise growth is illustrated. F-279 can be synthesized and isolated in high purity in milligram quantities using size exclusion chromatography, as evidenced by mass spectrometry. Electrospray ionization-mass spectrometry independently verifies the X-ray diffraction study based heavy atoms formula, Au279S84, and establishes the molecular formula with the complete ligands, namely, Au279(SPh-tBu)84. It is also the smallest gold nanocrystal to exhibit metallic behavior, with a surface plasmon resonance band around 510 nm.

Synthesis of Aromatic Thiolate-Protected Gold Nanomolecules by Core Conversion: The Case of Au36(SPh-tBu)24.

Ultrasmall nanomolecules (<2 nm) such as Au25(SCH2CH2Ph)18, Au38(SCH2CH2Ph)24, and Au144(SCH2CH2Ph)60 are well studied and can be prepared using established synthetic procedures. No such synthetic protocols that result in high yield products from commercially available starting materials exist for Au36(SPh-X)24. Here, we report a synthetic procedure for the large-scale synthesis of highly stable Au36(SPh-X)24 with a yield of ∼42%. Au36(SPh-X)24 was conveniently synthesized by using tert-butylbenzenethiol (HSPh-tBu, TBBT) as the ligand, giving a more stable product with better shelf life and higher yield than previously reported for making Au36(SPh)24 from thiophenol (PhSH). The choice of thiol, solvent, and reaction conditions were modified for the optimization of the synthetic procedure. The purposes of this work are to (1) optimize the existing procedure to obtain stable product with better yield, (2) develop a scalable synthetic procedure, (3) demonstrate the superior stability of Au36(SPh-tBu)24 when compared to Au36(SPh)24, and (4) demonstrate the reproducibility and robustness of the optimized synthetic procedure.

Transformation of Au144(SCH2CH2Ph)60 to Au133(SPh-tBu)52 Nanomolecules: Theoretical and Experimental Study.

Ultrastable gold nanomolecule Au144(SCH2CH2Ph)60 upon etching with excess tert-butylbenzenethiol undergoes a core-size conversion and compositional change to form an entirely new core of Au133(SPh-tBu)52. This conversion was studied using high-resolution electrospray mass spectrometry which shows that the core size conversion is initiated after 22 ligand exchanges, suggesting a relatively high stability of the Au144(SCH2CH2Ph)38(SPh-tBu)22 intermediate. The Au144 → Au133 core size conversion is surprisingly different from the Au144 → Au99 core conversion reported in the case of thiophenol, -SPh. Theoretical analysis and ab initio molecular dynamics simulations show that rigid p-tBu groups play a crucial role by reducing the cluster structural freedom, and protecting the cluster from adsorption of exogenous and reactive species, thus rationalizing the kinetic factors that stabilize the Au133 core size. This 144-atom to 133-atom nanomolecule's compositional change is reflected in optical spectroscopy and electrochemistry.

Au133(SPh-tBu)52 nanomolecules: X-ray crystallography, optical, electrochemical, and theoretical analysis.

Crystal structure determination has revolutionized modern science in biology, chemistry, and physics. However, the difficulty in obtaining periodic crystal lattices which are needed for X-ray crystal analysis has hindered the determination of atomic structure in nanomaterials, known as the "nanostructure problem". Here, by using rigid and bulky ligands, we have overcome this limitation and successfully solved the X-ray crystallographic structure of the largest reported thiolated gold nanomolecule, Au133S52. The total composition, Au133(SPh-tBu)52, was verified using high resolution electrospray ionization mass spectrometry (ESI-MS). The experimental and simulated optical spectra show an emergent surface plasmon resonance that is more pronounced than in the slightly larger Au144(SCH2CH2Ph)60. Theoretical analysis indicates that the presence of rigid and bulky ligands is the key to the successful crystal formation.