Overexpression of COL11A1 confers tamoxifen resistance in breast cancer.

Breast cancer is the most commonly diagnosed malignancy and benefits from endocrine agents such as tamoxifen. However, the development of drug resistance in cancerous cells often leads to recurrence, thus limiting the therapeutic benefit. Identification of potential biomarkers that can predict response to tamoxifen and recognize patients who will clinically benefit from this therapy is urgently needed. In this study, we report that high collagen type XI alpha 1 (COL11A1) expression was associated with poor therapeutic response and prognosis in breast cancer patients treated with tamoxifen. To confirm the role of COL11A1 in the development of tamoxifen resistance, we established MCF-7/COL11A1 and T47D/COL11A1 cell lines, which stably expressed COL11A1. Compared with parental MCF-7 and T47D, MCF-7/COL11A1 and T47D/COL11A1 cells were more resistant to 4-OHT-induced growth inhibition. Moreover, the level of COL11A1 expression was upregulated in tamoxifen-resistant MCF-7/TamR and T47D/TamR cell lines, and depletion of COL11A1 markedly sensitized the cells to 4-OHT in vitro and in vivo. Interestingly, the level of estrogen receptor α (ERα) expression was elevated, probably due to the increased COL11A1 in TamR cells. In addition, knockdown of COL11A1 decreased the expression of ERα and its downstream target genes. Overall, our findings suggest that overexpressed COL11A1 contributes to tamoxifen resistance, and targeting COL11A1 holds great promise for reversing endocrine resistance.

Mn-phenolic networks as synergistic carrier for STING agonists in tumor immunotherapy.

The cGAS-STING pathway holds tremendous potential as a regulator of immune responses, offering a means to reshape the tumor microenvironment and enhance tumor immunotherapy. Despite the emergence of STING agonists, their clinical viability is hampered by stability and delivery challenges, as well as variations in STING expression within tumors. In this study, we present Mn-phenolic networks as a novel carrier for ADU-S100, a hydrophilic STING agonist, aimed at bolstering immunotherapy. These nanoparticles, termed TMA NMs, are synthesized through the coordination of tannic acid and manganese ions, with surface modification involving bovine serum albumin to enhance their colloidal stability. TMA NMs exhibit pH/GSH-responsive disintegration properties, enabling precise drug release. This effectively addresses drug stability issues and facilitates efficient intracellular drug delivery. Importantly, TMA NMs synergistically enhance the effects of ADU-S100 through the concurrent release of Mn2+, which serves as a sensitizer of the STING pathway, resulting in significant STING pathway activation. Upon systemic administration, these nanoparticles efficiently accumulate within tumors. The activation of STING pathways not only induces immunogenic cell death (ICD) in tumor cells but also orchestrates systemic remodeling of the immunosuppressive microenvironment. This includes the promotion of cytokine release, dendritic cell maturation, and T cell infiltration, leading to pronounced suppression of tumor growth. Combining with the excellent biocompatibility and biodegradability, this Mn-based nanocarrier represents a promising strategy for enhancing tumor immunotherapy through the cGAS-STING pathway.

Poly-thymine DNA templated MnO2 biomineralization as a high-affinity anchoring enabling tumor targeting delivery.

Manganese oxide nanomaterials (MONs) are emerging as a type of highly promising nanomaterials for diseases diagnosis, and surface modification is the basis for colloidal stability and targeting delivery of the nanomaterials. Here, we report the in-situ functionalization of MnO2 with DNA through a biomineralization process. Using adsorption-oxidation method, DNA templated Mn2+ precursor to biomineralize into nano-cubic seed, followed by the growth of MnO2 to form cube/nanosheet hybrid nanostructure. Among four types of DNA homopolymers, poly-thymine (poly-T) was found to stably attach on MnO2 surface to resist various biological displacements (phosphate, serum, and complementary DNA). Capitalized on this finding, a di-block DNA was rationally designed, in which the poly-T block stably anchored on MnO2 surface, while the AS1411 aptamer block was not only an active ligand for tumor targeting delivery, but also a carrier for photosensitizer (Ce6) loading. Upon targeting delivery into tumor cells, the MnO2 acted as catalase-mimic nanozyme for oxygenation to sensitize photodynamic therapy, and the released Mn2+ triggered chemodynamic therapy via Fenton-like reaction, achieving synergistic anti-tumor effect with full biocompatibility. This work provides a simple yet robust strategy to functionalize metal oxides nanomaterials for biological applications via DNA-templated biomineralization.

Polyserotonin as a versatile coating with pH-responsive degradation for anti-tumor therapy.

Through self-polymerization of serotonin monomer, polyserotonin (PST) can coat on arbitrary surfaces with pH-responsive degradation, which was employed for nanoparticle coating and controlled drug release, achieving a robust anti-tumor effect when combined with its intrinsic photothermal effect.

Surface Coating of Pulmonary siRNA Delivery Vectors Enabling Mucus Penetration, Cell Targeting, and Intracellular Radical Scavenging for Enhanced Acute Lung Injury Therapy.

Pulmonary delivery of anti-inflammatory siRNA presents a promising approach for localized therapy of acute lung injury (ALI), while polycationic vectors can be easily trapped by the negatively charged airway mucin glycoproteins and arbitrarily internalized by epithelial cells with nontargetability for immunological clearance. Herein, we report a material, the dopamine (DA)-grafted hyaluronic acid (HA-DA), coating on an anti-TNF-α vector to address these limitations. HA-DA was simply synthesized and facilely coated on poly(ß-amino ester) (BP)-based siRNA vectors via electrostatic attraction. The resulting HA-DA/BP/siRNA displayed significantly enhanced mucus penetration, attributable to the charge screen effect of HA-DA and the bioadhesive nature of the grafting DA. After transmucosal delivery, the nanosystem could target diseased macrophages via CD44-mediated internalization and rapidly escape from endo/lysosomes through the proton sponge effect, resulting in effective TNF-α regulation. Meanwhile, DA modification endowed the coating material with robust antioxidative capability to scavenge a broad spectrum of reactive oxygen/nitrogen species (RONS), which protected the lung tissue from oxidative damage and synergized with anti-TNF-α to inhibit a cytokine storm. As a result, a remarkable amelioration of ALI was achieved in a lipopolysaccharide (LPS)-stimulated mice model. This study provides a multifunctional coating material to facilitate pulmonary drug delivery for the treatment of lung diseases.

New advances in brain-targeting nano-drug delivery systems for Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide and its incidence is increasing due to the ageing population. Currently, the main limitations of AD treatment are low blood-brain barrier permeability, severe off-target of drugs, and immune abnormality. In this review, four hypotheses for Alzheimer's pathogenesis and three challenges for Alzheimer's drug delivery are discussed. In addition, this article summarises the different strategies of brain targeting nano-drug delivery systems (NDDSs) developed in the last 10 years. These strategies include receptor-mediated (transferrin receptor, low-density lipoprotein receptor-related protein, lactoferrin receptor, etc.), adsorption-mediated (cationic, alkaline polypeptide, cell-penetrating peptides, etc.), and transporter-mediated (P-gp, GLUT1, etc.). Moreover, it provides insights into novel strategies used in AD, such as exosomes, virus-like particles, and cell membrane coating particles. Hence, this review will help researchers to understand the current progress in the field of NDDSs for the central nervous system and find new directions for AD therapy.HighlightsCharacteristics and challenges based on the pathogenesis of AD were discussed.Recent advances in novel brain-targeting NDDSs for AD over the past 10 years were summarised.

Polarity control of DNA adsorption enabling the surface functionalization of CuO nanozymes for targeted tumor therapy.

Nanomaterials with intrinsic catalytic activities (nanozyme) have drawn broad attention for various biomedical applications, with peroxidase-mimic nanozymes particularly attractive for cancer therapy due to their capability to catalyze the conversion of tumor-abundant H2O2 into more toxic hydroxyl radicals (˙OH) for effective tumor ablation. However, the facile surface modification of nanozymes for tumor-targeted delivery while retaining their catalytic activity remains a challenge. Here, we report an approach to functionalize the CuO nanozyme with DNA to enable targeted delivery and selective tumor destruction. We systematically studied the adsorption of DNA on the CuO surface, with special attention paid to the catalytic activity and DNA adsorption stability in the presence of various biological ligands. After gaining a fundamental understanding, a di-block DNA sequence was designed for adsorption on to the CuO surface, which allowed stable adsorption during in vivo circulation, passive accumulation into the tumor tissue, and the specific recognition of tumor cells, resulting in significant nanocatalytic tumor suppression in tumor xenograft mice models with no noticeable cytotoxicity. This work paves a way for the rational design of DNA-modified nanozymes for catalytic tumor therapy, and fundamentally, provides a new insight into the biointerface chemistry of CuO with DNA.

Nanoscale Copper(II)-Diethyldithiocarbamate Coordination Polymer as a Drug Self-Delivery System for Highly Robust and Specific Cancer Therapy.

Disulfiram (DSF), an old alcohol-aversion drug, has been repurposed for cancer therapy, and mechanistic studies reveal that it needs to be metabolized to diethyldithiocarbamate (DTC) and subsequently coordinates with copper(II) to form the DTC-copper complex (CuET) for anticancer activation. Here, we utilized this mechanism to construct a CuET self-delivery nanosystem based on the metal coordination polymer for highly robust and selective cancer therapy. In our design, the nanoparticles were facilely prepared under mild conditions by virtue of the strong coordination between Cu2+ and DTC, yielding 100% CuET loading capacity and allowing for further hyaluronic acid (HA) modification (CuET@HA NPs). The CuET@HA NPs could selectively deliver into cancer cells and release the active component of CuET in response to both endo/lysosome acidic pH and intracellular abundant GSH, which induces strong cytotoxicity toward cancer cells over normal cells taking advantage of the p97 pathway interference mechanism. Upon intravenous injection, the self-assembled system could passively accumulate into a tumor and elicit potent tumor growth inhibition at a dose of 1 mg/kg without any noticeable side effects. Given the cost-effective and easily scaled-up preparation, our designed nanosystem provides a promising strategy to pave the way for clinical translation of DSF-based cancer chemotherapy.

A tetrahedral DNA nanoflare for fluorometric determination of nucleic acids and imaging of microRNA using toehold strands.

The authors describe a tetrahedral DNA nanostructure loaded with SYBR Green (SG-TDN) for fluorometric determination of nucleic acids. After intercalating into the TDN, fluorescence of SG is enhanced by 260-fold (exc 480 nm, em 524 nm), and the resulting SG-TDN nanoflare displays >7-fold stronger fluorescence than that of FAM-labeled TDN. The SG-TDNs were coupled to magnetic microparticles and polydopamine nanoparticles to construct multi-functional nanoprobes through sequence hybridization using a toehold strand. The method was applied to detect a stretch of microRNA sequence (20 bp) in buffer and in undiluted serum with excellent selectivity, over a wide linear range and with a low limit of detection (0.2 nM). The probe was also applied for visualization of tumor-related microRNA in living cells via fluorescence imaging. Graphical abstract Schematic representation of tetrahedron-based DNA nanoflare for fluorometric nucleic acid determination in undiluted blood serum and living cells.

Ligands dissociation induced gold nanoparticles aggregation for colorimetric Al3+ detection.

Aluminum is a very important analyte, and developing biosensors for aluminum is an important analytical task. In this work, we report a novel mechanism to design colorimetric sensor based on gold nanoparticles (AuNPs). The AuNPs were prepared by reducing HAuCl4 using catechols, and the resulting AuNPs can be directly adapted for Al3+ detection without any post-modifications, showing high sensitivity and selectivity against other metal ions. Interestingly, our mechanistic studies revealed that Al3+-induced AuNPs aggregation was not due to the formation of interparticle crosslinks that refers to the design principle of most AuNPs-based colorimetric sensors reported before. But rather, Al3+ competitively coordinated with the capping ligands on AuNPs surface through the formation of stable Al-O bond, which dissociated these ligands from AuNPs surface. As a result, the AuNPs aggregated due to the loss of surface stabilizers. Based on this mechanism, several catechols, including pyrocatechol (PC), 3-(3,4-dihydroxyphenyl) propionic acid (DHCA), levodopa (LDA) and dopamine (DA), were used as reductant to prepare AuNPs for Al3+ sensing, and the AuNPs prepared by DA (AuNPs/DA) displayed the highest sensitivity, with detection limit of 0.81 µM. The sensor was then tested for Al content analysis in river water and food samples, and the results supported its practical applications. Importantly, this work expands the design principles for colorimetric sensors by using AuNPs.

Bioorthogonal DNA Adsorption on Polydopamine Nanoparticles Mediated by Metal Coordination for Highly Robust Sensing in Serum and Living Cells.

DNA-functionalized nanomaterials, such as various 2D materials, metal oxides, and gold nanoparticles, have been extensively explored as biosensors. However, their practical applications for selective sensing and imaging in biological samples remain challenging due to interference from the sample matrix. Bioorthogonal chemistry has allowed specific reactions in cells, and we want to employ this concept to design nanomaterials that can selectively adsorb DNA but not proteins or other abundant biomolecules. In this work, DNA oligonucleotides were found to be adsorbed on polydopamine nanoparticles (PDANs) via polyvalent metal-mediated coordination, and such adsorption bioorthogonally resisted DNA displacement by various biological ligands, showing better performance compared to graphene oxide and metal oxide nanoparticles for DNA detection. Using DNA/PDANs as biosensors, a detection limit of <1 nM target DNA was achieved in serum and other biological samples, and imaging of cancer-related microRNA in cells was demonstrated. The DNA binding mechanism on PDAN was further studied by ligand displacement experiments and X-ray photoelectron spectroscopy characterization, which demonstrated the critical role of polyvalent metal ions to bridge DNA with PDANs. This work provides fundamental insights into the biointerface science of PDANs with DNA, which can benefit applications in biosensor design, directed assembly of nanomaterials, bioimaging, and drug delivery.

A Facile Way to Increase the Cellular Uptake Efficiency of Hybrid Nanoparticles.

Lipid-polymer hybrid nanoparticles composed of polymer cores and lipid shells have been intensively studied as cancer drug delivery systems. The aim of the present study was to investigate the effect of phosphatidylcholine (PC) on physicochemical properties, stability and cellular uptake of lipid-poly(lactic-co-glycolic acid) (PLGA) hybrid nanoparticles. Coumarin-6 (cou-6) loaded hybrid nanoparticles (NPs) were prepared using PC with different alkyl chain lengths from C12 to C18, and were characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS), and encapsulation efficiency (EE). The quality and quantity of cellular uptake of NPs were carefully assessed. The NPs were 140-180 nm in size, negatively charged of 7-12 mV and with EE values higher than 80%. NPs remained stable in storage at 4 °C for 28 d. Cell viability rates of NPs were above 90%, and the as-prepared nanoparticles showed excellent biocompatibility by MTT assay. Interestingly, the uptake order was as follows: C12 < C14 < C16-C18. As the alkyl chain length of PC increased, the cellular uptake efficiency of hybrid nanoparticles was enhanced. C16 to C18 saturated PC exhibited the highest cellular uptake efficiency and did not significantly differ. PC had little or no effect on physicochemical properties and stability but did affect cellular uptake of hybrid nanoparticles. The obtained findings could provide a fundamental basis for rational design of hybrid nanoparticles and a facile way to improve the cellular uptake of hybrid nanoparticles.