Nanoplatform For Delivery Research Articles

Advancements in Engineering Tetrahedral Framework Nucleic Acids for Biomedical Innovations.

Tetrahedral framework nucleic acids (tFNAs) are renowned for their controllable self-assembly, exceptional programmability, and excellent biocompatibility, which have led to their widespread application in the biomedical field. Beyond these features, tFNAs demonstrate unique chemical and biological properties including high cellular uptake efficiency, structural bio-stability, and tissue permeability, which are derived from their distinctive 3D structure. To date, an extensive range of tFNA-based nanostructures are intelligently designed and developed for various biomedical applications such as drug delivery, gene therapy, biosensing, and tissue engineering, among other emerging fields. In addition to their role in drug delivery systems, tFNAs also possess intrinsic properties that render them highly effective as therapeutic agents in the treatment of complex diseases, including arthritis, neurodegenerative disorders, and cardiovascular diseases. This dual functionality significantly enhances the utility of tFNAs in biomedical research, presenting valuable opportunities for the development of next-generation medical technologies across diverse therapeutic and diagnostic platforms. Consequently, this review comprehensively introduces the latest advancements of tFNAs in the biomedical field, with a focus on their benefits and applications as drug delivery nanoplatforms, and their inherent capabilities as therapeutic agents. Furthermore, the current limitations, challenges, and future perspectives of tFNAs are explored.

Macrophage-T cell hybrid membrane-camouflaged biomimetic nanoparticles ameliorate autoimmune myocarditis via suppressing macrophage pyroptosis by target gene silencing

Abstract Background Current management of myocarditis mainly relies on conventional approaches and immunosuppressive therapies. However, these strategies often yield limited efficacy. Our previous research revealed the pivotal role of macrophage pyroptosis in myocarditis pathogenesis. Therefore, targeted intervention to inhibit macrophage pyroptosis may provide new insights into myocarditis treatment. Purpose We previously identified interferon regulatory factor 1 (IRF1) as the key modulator of macrophage pyroptosis in myocarditis. In this study, we synthesized a nano-delivery platform consisting of a macrophage-T cell hybrid membrane-coated zeolitic imidazolate framework-8 (ZIF-8) encapsulating IRF1-small interfering RNA (siRNA@ZIF@HM). We aimed to evaluate its targeting capability and therapeutic efficacy for macrophage pyroptosis in myocarditis. Methods The fabrication of siRNA@ZIF@HM was validated using transmission electron microscopy (TEM) and dynamic light scattering (DLS). Cellular uptake, cytotoxicity, endolysosome escape, IRF1 silencing, and anti-pyroptotic effect were assessed using mouse bone marrow-derived macrophages and the mouse macrophage cell line J774A.1 and RAW264.7. An experimental autoimmune myocarditis (EAM) mouse model was induced in Balb/c mice for in vivo investigations. Pharmacokinetics and targeting capability were determined with ex vivo fluorescence imaging and immunofluorescence staining. Subsequently, mice were randomly allocated into control, EAM + siRNA, EAM + siRNA@ZIF, and EAM + siRNA@ZIF@HM groups to assess the therapeutic efficacy. Additionally, the biodistribution and biosafety of siRNA@ZIF@HM were also evaluated. Results TEM, DLS, and element mapping confirmed the successful fabrication of siRNA@ZIF@HM, with a diameter of approximately 130 nm. The nanoparticle exhibited pH responsiveness and membrane markers of macrophage and T lymphocytes (Figure 1). It demonstrated high targeting specificity for pro-inflammatory macrophages and myocarditis. Immunofluorescence microscopy revealed successful endolysosome escape of IRF1-siRNA in macrophages. Consequently, the nanoparticle significantly silenced IRF1 protein expression and suppressed macrophage pyroptosis both in vivo and in vitro, resulting in the amelioration of autoimmune myocarditis (Figure 2). Furthermore, the nanoparticle showed good biocompatibility with no significant changes observed in other organs. Conclusions The pH-responsive, macrophage-T cell hybrid membrane-coated biomimetic nanoparticle demonstrates promising capability for targeted siRNA delivery to myocardial inflammation sites, particularly pro-inflammatory macrophages. Additionally, targeting IRF1-mediated macrophage pyroptosis represents a potential therapeutic strategy for myocarditis treatment.Figure 1Figure 2

Chemotherapeutic Drug Delivery Nanoplatform Development: From Physicochemical to Preclinical Evaluation.

Through this study, the synergistic behavior of small-molecular-weight, amphiphilic surfactant molecules and the triblock copolymer Pluronic 188 was extensively evaluated based on their ability to formulate nanocarriers with novel properties for the delivery of class II and IV (biopharmaceutical classification system) chemotherapeutic compounds. The combination of four different surfactants at multiple weight ratios and twelve initially formulated nanosystems resulted in four hybrid delivery platforms, which were further studied in terms of multiple physicochemical characteristics, as well as their stability in protein-rich media (fetal bovine serum/phosphate-buffer saline). Finally, we obtained a single final nanoformulation that exhibited a high loading capacity (%EE ≥ 75%) and a sustained drug release profile under physiological conditions (model drug methotrexate), without altering the original physicochemical characteristics of the carrier. With a mean hydrodynamic radius (Rh) of less than 70 nm, a polydispersity index of 0.219, and no protein complexation, the system is a suitable candidate for in vivo, intravenous, and/or intramuscular administration. The cytotoxicity and genotoxicity of both loaded and unloaded carriers were evaluated through the examination of the upregulation or downregulation of apoptosis-related pathways. Multiple conventional 2D and 3D spheroidal conformations were used for these assessments, including HEK293, HCT-116, and MCF-7 cell lines, the results of which stressed the safety and biocompatibility of the empty nanocarrier. Additionally, experiments on Caenorhabditis elegans were conducted to evaluate the system's in vivo toxicity, focusing on developmental stages, egg-laying behavior, and locomotion. Nanosystems studied in terms of chemotherapeutic encapsulation have mostly focused on the physiochemical aspect of the development of such novel delivery platforms, with only few exceptions proceeding step-by-step from cellular 2D to 3D to in vivo experimentation. The present study offers a holistic view of the behavior of such a novel system, advancing our understanding of the capabilities of polymeric/surfactant-based nanodelivery platforms.

Developing Porous Protein Cage Nanoparticles as Cargo-Loadable and Ligand-Displayable Modular Delivery Nanoplatforms.

Protein cage nanoparticles, self-assembled from protein subunits, provide distinct exterior and interior spaces and can carry diagnostic and/or therapeutic cargo agents through chemical conjugation, in vitro disassembly/reassembly process, or assembly-mediated encapsulation. Here, we developed porous SpyCatcher-mi3 (SC-mi3) as modular delivery nanoplatforms, capable of loading cargos through pores and displaying targeting ligands using SpyCatchers (SC) as anchors for SpyTagged (ST) ligands. Fluorescent dyes (F5M and A647) and a pH-sensitive prodrug (Aldox) were conjugated to the interior surface cysteines of SC-mi3, forming F5M@SC-mi3, A647@SC-mi3, and Aldox@SC-mi3. Subsequently, EGFR-binding affibody molecules (EGFRAfb) were displayed on the exterior surface of F5M@SC-mi3 and Aldox@SC-mi3 using the SC/ST protein ligation system, forming F5M@mi3/EGFRAfb and Aldox@mi3/EGFRAfb, respectively. F5M@mi3/EGFRAfb selectively bound to EGFR-overexpressing MDA-MB-468 cells, visualizing the target cancer cells, while Aldox@mi3/EGFRAfb selectively delivered doxorubicin, leading to target-specific cancer cell death. To encapsulate large proteins within SC-mi3, biotins were initially conjugated to the interior surface (BPM@SC-mi3) and mSA2-fused protein cargo molecules (mSA2-HaloTag and mSA2-yCD) were successfully introduced through the pores and securely encapsulated, forming TMR-H@SC-mi3 and yCD@SC-mi3, respectively. Subsequent display of EGFRAfb on their surface allowed the visualization of target cancer cells using fluorescent HaloTag ligand labeling and facilitated the killing of target cancer cells by converting the prodrug 5-FC to the cytotoxic drug 5-FU. Modular functionalization of the two distinct spaces in porous SC-mi3 may offer opportunities for developing target-specific functional cargo-delivery nanoplatforms in biomedical fields.

B-179 Comparative Evaluation of Cisplatin Release from Alginate Hydrogels with Embedded Silver Nanoparticles: An HPLC and Colorimetric Spectrophotometry Study

Abstract Background Cisplatin [cis-dichlorodiamine platinum (II)], is a well-recognized chemotherapeutical drug. Cisplatin has been employed in treating a wide range of human cancers, such as those of the breast, bladder, lung, ovarian, and testicular cancers. Its therapeutic action is attributed to its capacity to form crosslinks with the DNA's purine bases, disrupting DNA repair processes, causing DNA damage, and ultimately leading to apoptosis in cancerous cells. Nonetheless, the application of cisplatin is constrained by the development of multidrug resistance and the occurrence of severe adverse effects, including nephrotoxicity, bone marrow suppression, hearing loss, allergic responses, nerve damage, and low magnesium levels in the blood. Numerous strategies have been explored to enhance the anticancer effectiveness of cisplatin while minimizing its associated toxicities. These strategies include combination therapies that incorporate nanoparticles, liposomes, and polymer micelles. In this project, cisplatin was embedded into alginate hydrogels loaded with silver nanoparticles and in vitro cisplatin release study using HPLC and UV-Vis spectrophotometry were studied. Methods We developed a novel nanocomplex by integrating silver nanoparticles (AgNPs) with alginate hydrogel coating to create a versatile platform for drug delivery. To incorporate the chemotherapeutic agent, cisplatin (150 ppm) was introduced into the AgNPs-alginate mixture utilizing rapid stirring to ensure uniform distribution and encapsulation of cisplatin within the nanocomplex. A range of analytical methods, such as UV-Vis, FTIR, SEM/EDX, and Zeta potential analysis, were employed to characterize the nanocomplex. To evaluate cisplatin release kinetics from the nanocomplex, we employed an in vitro dialysis method for monitoring its sustained release. High-performance liquid chromatography (HPLC) was used for precise cisplatin release quantification, then validated by colorimetric spectrophotometry. This dual-method approach ensured accurate insights into the nanocomplex’s release dynamics, substantiating its potential in enhancing targeted cancer therapy through advanced drug delivery systems. Results The analysis through UV-Vis revealed an absorption spectrum around 410 nm, indicative of the characteristic plasmon resonance associated with silver nanoparticles. TEM provided high-resolution imagery, revealing that the size of the silver nanoparticles varied between 4 and 30 nm, averaging at 13 nm with a standard deviation of 5 nm specifically for the alginate-coated AgNPs. SEM images confirmed the anticipated spherical distribution of silver nanoparticles within the alginate hydrogel framework. EDX spectroscopy analysis further verified the incorporation of silver nanoparticles and platinum within the complex. The cisplatin release studies from this newly developed nanocomplex illustrated a prolonged, slow, and consistent release pattern, extending over days, in stark contrast to the rapid and complete release of cisplatin from its unbound state, which achieved peak release within an hour. Conclusions In this study, we successfully developed and validated an innovative, multifunctional nanoplatform for drug delivery, comprising alginate hydrogel synergistically co-loaded with silver nanoparticles (AgNPs) and cisplatin. This novel drug carrier system demonstrated a marked enhancement in the controlled delivery of cisplatin, evidenced by the slow and sustained release profile observed over three days. The slow and sustained release of cisplatin from the alginate complex, compared to the free form, highlights the efficacy of the nanoplatform in modulating the drug’s release kinetics.

Bio-Inspired Nanodelivery Platform: Platelet Membrane-Cloaked Genistein Nanosystem for Targeted Lung Cancer Therapy.

Genistein (Gen), a natural polyphenolic compound, has emerged as a promising candidate for lung cancer treatment. However, the potential clinical application of Gen is limited due to its poor solubility, low bioavailability, and toxic side effects. To address these challenges, a biomimetic delivery platform with cell membranes derived from natural cells as carrier material was constructed. This innovative approach aims to facilitate targeted drug delivery and solve the problem of biocompatibility of synthetic materials. First, the liposomes (LPs) loaded with Gen (LPs@Gen) was prepared using the ethanol injection method. Subsequently, PLTM-LPs@Gen was obtained through co-extrusion after mixing platelet membrane (PLTM) and LPs@Gen. Additionally, the biological and physicochemical properties of PLTM-LPs@Gen were investigated. Finally, the targeting ability, therapeutic efficacy, and safety of PLTM-LPs@Gen for lung cancer were evaluated using both a cell model and a tumor-bearing nude mouse model. The optimal preparation ratio for LPs@Gen was Gen: soybean lecithin: cholesterol: DSPE-PEG2000 (3:30:5:10, mass ratio), while the ideal fusion ratio of LPs@Gen and PLTM was 1:1. The particle size of PLTM-LPs@Gen was 108.33 ± 1.06 nm, and the encapsulation efficiency and drug loading were 94.29% and 3.09% respectively. Gen was released continuously and slowly from PLTM-LPs@Gen. Moreover, PLTM-LPs@Gen exhibited good stability within one week. The results of in vitro cellular uptake and in vivo distribution experiments indicated that the carrier material, PLTM-LPs, has the immune escape ability and tumor targeting ability. Consequently, it showed better therapeutic effects than free drugs and traditional LPs in vitro and in vivo tumor models. In addition, safety experiments demonstrated that PLTM-LPs@Gen possesses good biocompatibility. Biomimetic nanomedicine provides a new strategy for the precision treatment of lung cancer in clinical practice.

Polyphenol-Based Self-Assembled Nanomedicine for a Three-Pronged Approach to Reversing Tumor Immunosuppression.

The challenges of multi-pathway immune resistance and systemic toxicity caused by the direct injection of immune checkpoint inhibitors are critical factors that compromise the effectiveness of clinical immune checkpoint blockade therapy. In this context, natural polyphenols have been employed as the primary component to construct a targeted and acid-responsive PD-L1 antibody (αPD-L1) delivery nanoplatform. This platform incorporates garcinol, an inhibitor of the Nuclear Factor Kappa-B (NF-κB) signaling pathway, to regulate pro-tumor immune escape cytokines and regulatory T cells. Additionally, the nanoplatform has been verified to induce immunogenic cell death (ICD), which promotes the maturation of dendritic cells and enhances the activity of cytotoxic T lymphocytes. In vivo and in vitro experimental results demonstrated that the nanoplatform can boost the immune response through a PD-L1 and NF-κB blocking/ICD inducing three-pronged strategy, thereby effectively combating tumor growth and metastasis.

Nanoparticle Delivery of an Oligonucleotide Payload in a Glioblastoma Multiforme Animal Model.

Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain malignancy for which there is no cure. The blood-brain barrier is a significant hurdle in the delivery of therapies to GBM. Reported here is an image-guided, iron oxide-based therapeutic delivery nano platform capable of bypassing this physiological barrier by virtue of size and accumulating in the tumor region, delivering its payload. This 25 nm nano platform consists of crosslinked dextran-coated iron oxide nanoparticles labeled with Cy5.5 fluorescent dye and containing antisense oligonucleotide as a payload. The magnetic iron oxide core enables tracking of the nanoparticles through in vivo magnetic resonance imaging, while Cy5.5 dye allows tracking by optical imaging. This report details the monitoring of the accumulation of this nanoparticle platform (termed MN-anti-miR10b) in orthotopically implanted glioblastoma tumors following intravenous injection. In addition, it provides insight into the in vivo delivery of RNA oligonucleotides, a problem that has hampered the translation of RNA therapeutics into the clinic.

Preparation and effects of functionalized liposomes targeting breast cancer tumors using chemotherapy, phototherapy, and immunotherapy

Breast cancer therapy has significantly advanced by targeting the programmed cell death-ligand 1/programmed cell death-1 (PD-L1/PD-1) pathway. BMS-202 (a smallmolecule PD-L1 inhibitor) induces PD-L1 dimerization to block PD-1/PD-L1 interactions, allowing the T-cell-mediated immune response to kill tumor cells. However, immunotherapy alone has limited effects. Clinically approved photodynamic therapy (PDT) activates immunity and selectively targets malignant cells. However, PDT aggravates hypoxia, which may compromise its therapeutic efficacy and promote tumor metastasis. We designed a tumor-specific delivery nanoplatform of liposomes that encapsulate the hypoxia-sensitive antitumor drug tirapazamine (TPZ) and the small-molecule immunosuppressant BMS. New indocyanine green (IR820)-loaded polyethylenimine-folic acid (PEI-FA) was complexed with TPZ and BMS-loaded liposomes via electrostatic interactions to form lipid nanocomposites. This nanoplatform can be triggered by near-infrared irradiation to induce PDT, resulting in a hypoxic tumor environment and activation of the prodrug TPZ to achieve efficient chemotherapy. The in vitro and in vivo studies demonstrated excellent combined PDT, chemotherapy, and immunotherapy effects on the regression of distant tumors and lung metastases, providing a reference method for the preparation of targeted agents for treating breast cancer.Graphical abstract

Targeted quercetin delivery nanoplatform via folic acid-functionalized metal-organic framework for alleviating ethanol-induced gastric ulcer

Gastric ulcers, often caused by factors such as ethanol consumption and Helicobacter pylori infection, present significant treatment challenges due to the limited efficacy and adverse effects of current therapies. This study aimed to develop a nanoscale quercetin (Qu) delivery system using folic acid (FA)-functionalized cyclodextrin-based metal–organic frameworks (CD-MOFs), termed Qu@FA-CMOF nanoplatforms, to enhance therapeutic outcomes for acute gastric ulcers. The FA modification endowed the nanoplatforms with targeted delivery capabilities, improving cellular uptake and facilitating the sustained release of Qu. Comprehensive in vitro and in vivo evaluations demonstrated that Qu@FA-CMOF significantly attenuated gastric tissue injury, reduced oxidative stress, and suppressed inflammation by modulating the Nrf2/HO-1 and COX-2/NF-κB signaling pathways. Furthermore, the nanoplatform exhibited potent anti-apoptotic effects through regulation of the Bax/Bcl-2 pathway, and showed favorable biocompatibility with no significant toxicity observed in major organs. These findings highlight the potential of Qu@FA-CMOF nanoplatforms as a safe and effective therapeutic strategy for ethanol-induced gastric injury, offering a promising avenue for future nanomedicine-based therapies in gastric ulcer treatment.

ZIF-8 as a pH-Responsive Nanoplatform for 5-Fluorouracil Delivery in the Chemotherapy of Oral Squamous Cell Carcinoma.

5-fluorouracil (5-FU), a chemotherapeutic agent against oral squamous cell carcinoma (OSCC), is limited by poor pharmacokinetics and toxicity. The pH-sensitive zeolite imidazolate framework-8 (ZIF-8) may increase the selectivity and length of 5-FU released into the acidic tumor microenvironment. This study examined the in vitro 5-FU absorption and release profiles of ZIF-8, and then progressed to cytotoxicity assays using the OSCC primary cell line SCC7. The 5-FU loading capacity of ZIF-8 was calculated with UV-vis spectroscopy (λ = 260 nm). 5-FU release was quantified by submerging 5-FU@ZIF-8 in pH 7.4 and 5.5 acetate buffer over 48 h. For the cytotoxicity assays, 5-FU, ZIF-8, and 5-FU@ZIF-8 were added to SCC7 cultures at 25, 50, and 100 μg/mL. Cell viability was assessed through toluidine blue staining and further quantified through transcriptomic RNA sequencing. ZIF-8 stabilized at a maximum absorption of 2.71 ± 0.22 mg 5-FU, and released 0.66 mg more 5-FU at pH 5.5 than 7.4 for at least 72 h. The cytotoxicity assays showed that 5-FU@ZIF-8 had a synergistic inhibitory effect at 50 μg/mL. The RNA sequencing analysis further revealed the molecular targets of 5-FU@ZIF-8 in SCC7. 5-FU@ZIF-8 may release 5-FU based on the pH of the surrounding microenvironments and synergistically inhibit OSCC.

Cyclic RGD conjugated PEG-PLGA nanoparticle enhances preventative effect of bilirubin on the development of ultraviolet-B (UVB)-induced cataract

Age related cataract (ARC) is characterized by protein conformational disorder with aging stands out as an independent risk factor. Therefore, mitigation of oxidative stress and DNA damage within the lens emerges as a potential therapeutic strategy. While topical administration remains the most common treatment modality for ocular disorder, drug bioavailability is hindered by the cornea epithelium barrier. In this study, we developed a novel cyclic Arg-Gly-Asp (cRGD)-conjugated nanoparticle encapsulating bilirubin (cRNM@BR), an endogenous antioxidant, to combat against cellular senescence and lens opacity associated with ARC. Immunofluorescence staining assay confirmed that cRGD modification significantly prolonged nanoparticle retention on the ocular surface by targeting integrin expressed on corneal epithelium. Moreover, through LC-MS/MS analysis, we demonstrated the enhanced transcorneal penetration efficacy of cRGD-modified nanodrugs both in vivo and in vitro. Our mechanistic investigations revealed that cRNM entered human corneal epithelial cells (HCECs) by clathrin and micropinocytosis-mediated pathways, with the ER/Golgi pathway facilitating its exocytosis. In a mouse model of ultraviolet B (UVB)-induced cataract, topical application of cRNM@BR effectively alleviated intracellular reactive oxygen species (ROS) levels and DNA damage in lens epithelial cells (LECs), thereby preventing cellular senescence and lens opacity. Transcriptomics analysis of LECs in UVB-exposed group and cRNM@BR pretreated group indicated significant enrichment of the cGAS/STING pathway. Further experiments determined that cRNM@BR prevented cellular senescence and lens opacity by ameliorating the cGAS/STING pathway. In conclusion, our findings underscore the therapeutic potential of cRNM@BR in ARC management and highlight the efficacy of cRGD-conjugated nanoplatform for intraocular delivery.

Hierarchical Chitin Nanocrystal-Based 3D Printed Dual-Layer Membranes Hydrogels: A Dual Drug Delivery Nano-Platform for Periodontal Tissue Regeneration.

Periodontitis, a prevalent chronic inflammatory disease caused by bacteria, poses a significant challenge to current treatments by merely slowing their progression. Herein, we propose an innovative solution in the form of hierarchical nanostructured 3D printed bilayer membranes that serve as dual-drug delivery nanoplatforms and provide scaffold function for the regeneration of periodontal tissue. Nanocomposite hydrogels were prepared by combining lipid nanoparticle-loaded grape seed extract and simvastatin, as well as chitin nanocrystals, which were then 3D printed into a bilayer membrane that possesses antimicrobial properties and multiscale porosity for periodontal tissue regeneration. The constructs exhibited excellent mechanical properties by adding chitin nanocrystals and provided a sustained release of distinct drugs over 24 days. We demonstrated that the bilayer membranes are cytocompatible and have the ability to induce bone-forming markers in human mesenchymal stem cells, while showing potent antibacterial activity against pathogens associated with periodontitis. In vivo studies further confirmed the efficacy of bilayer membranes in enhancing alveolar bone regeneration and reducing inflammation in a periodontal defect model. This approach suggests promising avenues for the development of implantable constructs that not only combat infections, but also promote the regeneration of periodontal tissue, providing valuable insights into advanced periodontitis treatment strategies.

PLGA Nanoplatform for the Hypoxic Tumor Delivery: Folate Targeting, Therapy, and Ultrasound/Photoacoustic Imaging.

Effective targeting of breast tumors is critical for improving therapeutic outcomes in breast cancer treatment. Additionally, hypoxic breast cancers are difficult to treat due to resistance toward chemotherapeutics, poor vascularity, and enhanced angiogenesis, which complicate effective drug delivery and therapeutic response. Addressing this formidable challenge requires designing a drug delivery system capable of targeted delivery of the anticancer agent, inhibition of efflux pump, and suppression of the tumor angiogenesis. Here, we have introduced Palbociclib (PCB)-loaded PLGA nanoparticles (NPs) consisting of chitosan-folate (CS-FOL) for folate receptor-targeted breast cancer therapy. The developed NPs were below 219 nm with a smooth, spherical surface shape. The entrapment efficiencies of NPs were achieved up to 85.78 ± 1.8%. Targeted NPs demonstrated faster drug release at pH 5.5, which potentiated the therapeutic efficacy of NPs due to the acidic microenvironment of breast cancer. In vitro cellular uptake study in MCF-7 cells confirmed the receptor-mediated endocytosis of targeted NPs. In vivo ultrasound and photoacoustic imaging studies on rats with hypoxic breast cancer showed that targeted NPs significantly reduced tumor growth and hypoxic tumor volume, and suppressed angiogenesis.

Use of a novel proteomimetic nanoplatform for simultaneous delivery of antigens with adjuvants to impact tumor growth in multiple tumor models.

40 Background: Patient-specific cancer vaccines derived from tumor antigen have been explored as a promising therapeutic strategy, however, challenges delivering vaccine components in a coordinated fashion to elicit antitumor responses remain. To overcome these, we utilize a novel nanoplatform called the Protein-Like Polymer (PLP), which allows for sustained and targeted delivery of tumor antigens in conjunction with adjuvants. Methods: PLPs containing peptide antigens were synthesized via ROMP and characterized. A library of compounds with different sidechain linkage chemistries, degrees of polymerization (DP), and inclusion/exclusion of Oligo-ethylene glycol (OEG) were made to determine design rules for immune activation. Cell uptake and functional assays using payload-specific T Cells were conducted. Immunization in three independent tumor models was done to show generalizability. Ability of PLPs to co-deliver adjuvants was tested by electrostatically coupling small molecule STING agonist, 2’3’ cGAMP. Results: Conjugating antigens to the polymer via a cleavable disulfide linkage, which reduces intracellularly in APCs, resulted in increased endosomal localization, higher levels of induced T cell proliferation, cytokine production, and expression of activation markers in CTLs and APCs. Incorporating a diluent amount of OEG side chains reduced enzymatic degradation while increasing immunogenicity and uptake. Additionally, increasing the DP, and therefore the density of antigen side chains, further improved vaccine efficacy and resistance to proteolysis. Antigen-PLP conjugates enhanced dendritic cell activation and T-cell response only when paired with cells from their cognate system, with no activity in immune cells not expressing receptors for the payload demonstrating antigen-specificity. Mice bearing established B16F10, MC38, or TC-1 tumors treated with PLPs containing gp100, adpgk, or E7 respectively all showed increased survival times, reduced tumor burden with corresponding changes in immune cell profiles, and immunological memory upon rechallenge. Impressively, mice treated with STING-PLP complexes had significantly smaller tumors vs control at day 14 (0.038g vs 0.76g; p < 0.0001) and allowed for subcutaneous administration of 2’3’ cGAMP, which traditionally requires intratumoral injection. Studies on the effects of vaccinating with pools of neoantigens multiplexed onto one PLP are ongoing. Conclusions: This work validates the ability of PLPs to overcome major limitations in cancer vaccine development. The modularity of the platform allows for complex nano-architectures including systems capable of delivering challenging compounds, ie small molecule STING agonists, subcutaneously through electrostatic coupling, highlighting its potential to revolutionize cancer vaccinology.

Formulation of double microemulsion based on pH-responsive PEG/PVA/zinc oxide as a potential nano-platform for drug delivery: Green synthesis, and physico-chemical characterization

The current workdeveloped a novel kind of pH-sensitive nanocarrier by combining a hydrogel nanocomposite composed of polyethylene glycol (PEG), polyvinyl alcohol (PVA), and zinc oxide nanoparticles (ZnO NPs) with an extensive surface area.To provide quality control, the nanocarriers were synthesizedusing the water/oil/water (W/O/W) emulsifying method to deliver quercetin (QC). Considering the compelling possibility of QCas a cancer treatment, it is imperative to overcome the challenges associated with its rapid release and poor solubility. X-ray diffraction (XRD) and Fourier-transform infrared spectroscopy (FT-IR) were used to assess the nanocarrier’s crystalline structure and component interactions.The scanning electron microscopy (SEM) illustrationsconfirmed the surface uniformity of the nanocarrier and its spherical morphology. Dynamic light scattering (DLS) and zeta potential provide information on the nanocarrier’saveragesize, surface charge, and stability variations.High QC loading and encapsulationefficiencies were obtained, which were further improved uponaddition of ZnO NPs.The release kinetics of drug-loaded PEG/PVA/ZnO nanocomposites were investigated at pH=5.4 and pH=7.4, revealing an excellent controlledpH-sensitive release profile.The in vitro cytotoxicity of the nanocomposites was evaluated by MTT assay.As a result, a diminution in the total number of viableMCF-7 breast cancer cells when subjected to PEG/PVA/ZnO nanocomposites, compared with PEG/PVAsamples and the control groupsample, suggests that the addition of ZnO NPs has improved the cytotoxic activity of the nanocomposite.Hence, applyingPEG/PVA hydrogel encapsulated with ZnO NPs demonstrates significant promise inpH-sensitivecontrolled drug release.

Surface Engineering of Two-Dimensional Black Phosphorus for Advanced Nanophotonics.

ConspectusEverything in the world has two sides. We should correctly understand its two sides to pursue the positive side and get rid of the negative side. Recently, two-dimensional (2D) black phosphorus (BP) has received a tremendous amount of attention and has been applied for broad applications in optoelectronics, transistors, logic devices, and biomedicines due to its intrinsic properties, e.g., thickness-dependent bandgap, high mobility, highly anisotropic charge transport, and excellent biodegradability and biocompatibility. On one hand, rapid degradation of 2D BP under ambient conditions becomes a vital bottleneck that largely hampers its practical applications in optical and optoelectronic devices and photocatalysis. On the other hand, just because of its ambient instability, 2D BP as a novel kind of nanomedicine in a cancer drug delivery system can not only satisfy effective cancer therapy but also enable its safe biodegradation in vivo. Until now, a variety of surface functionality types and approaches have been employed to rationally modify 2D BP to meet the growing requirements of advanced nanophotonics.In this Account, we describe our research on surface engineering of 2D BP in two opposite ways: (i) stabilizing 2D BP by various approaches for advanced nanophotonic devices with both remarkable photoresponse behavior and environmentally structural stability and (ii) making full use of biodegradation, biocompatibility, and biological activity (e.g., photothermal therapy, photodynamic therapy, and bioimaging) of 2D BP for the construction of high-performance delivery nanoplatforms for biophotonic applications. We highlight the targeted aims of the surface-engineered 2D BP for advanced nanophotonics, including photonic devices (optics, optoelectronics, and photocatalysis) and photoinduced cancer therapy, by means of various surface functionalities, such as heteroatom incorporation, polymer functionalization, coating, heterostructure design, etc. From the viewpoint of potential applications, the fundamental properties of surface-engineered 2D BP and recent advances in surface-engineered 2D BP-based nanophotonic devices are briefly discussed. For the photonic devices, surface-engineered 2D BP can not only effectively improve environmentally structural stability but also simultaneously maintain photoresponse performance, enabling 2D BP-based devices for a wide range of practical applications. In terms of the photoinduced cancer therapy, surface-engineered 2D BP is more appropriate for the treatment of cancer due to negligible toxicity and excellent biodegradation and biocompatibility. We also provide our perspectives on future opportunities and challenges in this important and fast-growing field. It is envisioned that this Account can attract more attention in this area and inspire more scientists in a variety of research communities to accelerate the development of 2D BP for more widespread high-performance nanophotonic applications.

Exploring MIL-68(Al) nanocarrier for melatonin delivery: probing pro-oxidant effects in cancer cells and achieving sustained drug release

This study explored the synthesis of MIL-68(Al), characterized its properties, and investigated its ability to encapsulate and release melatonin (MEL) in response to changes in pH, intending to develop a more effective drug delivery system. Analyses were directed to characterize the designed nanocarriers before and after drug loading. The drug loading efficiency (DLE) and drug loading content (DLC) of MIL-68(Al) were 78.8% and 44.0%, respectively. The extended drug release period of MEL@MIL-68(Al) was observed to exhibit a faster release under acidic conditions compared to neutral conditions. The cell treatment with free MEL, MIL-68(Al), and MEL@MIL-68(Al) was completed, and a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed at lung cancer A549 cells and normal fibroblastic MRC-5 cells for the cytotoxicity study. MEL@MIL-68(Al) was more cytotoxic than MIL-68(Al) in A549 cells. Analyzing reactive oxygen species (ROS) levels via fluorescent microscopic analysis showed ROS overproduction in cells treated with MEL@MIL-68(Al) in comparison to other interventions. Additionally, MEL@MIL-68(Al) modulated the protein expression levels of Nrf-2, Keap-1, and HO-1 in cells. Therefore, MEL@MIL-68(Al) exerts its potent anticancer effects via ROS overproduction and downregulation of the Nrf2/Keap-1 pathway. Therefore, this system can be a promising nanoplatform for the successful delivery of MEL and potentiating its anticancer effects.

Light-Enhanced Tandem-Responsive Nano Delivery Platform for Amplified Anti-tumor Efficiency.

Designing nanomedicines with low toxicity, high targeting, excellent therapeutic effects, and precise release is always the major challenges in clinical cancer treatment. Here, we report a light-enhanced tandem-responsive nano delivery platform COF-B@X-03 for amplified anti-tumor efficiency. Biotin-loaded COF-B@X-03 could precisely target tumor cells, and the azo and hydrazone bonds in it would be depolymerized by the overexpressed azoreductase and acidic microenvironment in hypoxic tumors. In vitro experimental results indicate mitochondrial and endoplasmic reticulum stress caused by COF-B@X-03 under light is the direct cause of tumor cell death. In vivo experimental data prove COF-B@X-03 achieves low oxygen dependent phototherapy, and the maintenance of intratumoral hypoxia provides the possibility for the continuous degradation of COF-B@X-03 to generate more reactive oxygen species for tumor photodynamic therapy by released X-03. In the end, COF-B@X-03 phototherapy group achieves higher tumor inhibition rate than X-03 phototherapy group, which is 81.37 %. Meanwhile, COF-B@X-03 significantly eliminates the risk of tumor metastasis. In summary, the construction of this tandem-responsive nano delivery platform provides a new direction for achieving efficient removal of solid tumors in clinical practice.

NIR-light controlled local delivery of nitric oxide based on self-targeting carbon dots

Nitric oxide (NO)-based gas therapy has received ever-increasing attention in treatment of many diseases, especially cancer. However, the selective organelle targeted delivery and controllable release of NO remains highly desirable. In this work, a sequentially targeting delivery nanoplatform has been constructed by encapsulating heat-responsive S-nitrosocysteine (the NO donor, SNC) conjugated mitochondria-targeting carbon dots (MitoCDs) and indocyanine green (ICG) within liposomes which are further modified with aptamer that can specifically bind to nucleolin overexpressed on the surface of several cancer cells. MitoCDs were prepared via one-step hydrothermal reaction using citric acid and m-diethylaminophenol as starting materials and used without any external targeting molecules. ICG molecules were employed as NIR-triggered photothermal agent followed by NO precisely controlled release in mitochondria. By combining gas and photothermal treatment, the nanocarrier produced a synergistic and superior killing effect on several cancer cell lines. And the cell growth inhibition of NCL-CSI@Lip on HEp-2 cells raised up to 72.39 %. Such an ‘all-in-one’ mitochondria-targeted NO nanocarrier may lead to new way for overcoming the problem of multidrug resistance in intracellular drug delivery.