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Synthetic carriers that enable site-specific intracellular delivery of proteins are valuable in many biomedical applications. Aldehyde-displaying silica nanoparticles (MSN-aldehyde) containing lysosome activatable rhodamine-lactams were prepared for fluorescent tracking and delivery of proteins via lysosomal acidity-triggered release of proteins an...
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... (Fig. 2). The decreased zeta potential of MSN-alde- hyde (À34 mV) relative to MSN-amine (49 mV) suggested effi- cient pegylation of MSN-amine (Fig. 2). FTIR spectroscopy analysis revealed the occurrence of a stretch peak at 1716 cm À1 in MSN-aldehyde as compared to pegylated MSN-amine, indi- cating the presence of aldehyde groups on MSN-aldehyde (Fig. ...
Citations
... Regarding GFP, many works have described its covalent [74,75] and non-covalent [76,77] encapsulation in silica based nanomaterials to produce hybrid nanomaterials with diverse applications as fluorescent probes. However, there are no works describing detailed experimental characterizations of GFP adsorption onto silica based materials and the influence of physicochemical parameters such as pH or ionic strength, to the best of our knowledge. ...
We develop a molecular thermodynamic theory to study the interaction of some proteins with a charge regulating silica-like surface under a wide range of conditions, including pH, salt concentration and protein concentration. Proteins are modeled using their three dimensional structure from crystallographic data and the average experimental pKa of amino acid residues. As model systems, we study single-protein and binary solutions of cytochrome c, green fluorescent protein (GFP), lysozyme and myoglobin. Our results show that protonation equilibrium plays a critical role in the interactions of proteins with these type of surfaces. The terminal hydroxyl groups on the surface display considerable extent of charge regulation; protein residues with titratable side chains increase protonation according to changes in the local environment and the drop in pH near the surface. This behavior defines protein-surface interactions and leads to the emergence of several phenomena: (i) a complex non-ideal surface charge behavior; (ii) a non-monotonic adsorption of proteins as a function of pH; and (iii) the presence of two spatial regions, a protein-rich and a protein-depleted layer, that occur simultaneously at different distances from the surface when pH is slightly above the isoelectric point of the protein. In binary mixtures, protein adsorption and surface-protein interactions cannot be predicted from single-protein solution considerations.
... [38] While the addition of bovine serum albumin (BSA) significantly increased the release of OVAp, the P-CDM-OVAp released less than 10% OVAp after 24 h at acidic conditions, which may limit CTL activation. [38] As an alternative to the CDM linker, the acidresponsive imine bond (Schiff-base) formed between aldehyde and amine is of great interest, [39][40][41][42][43] which can be utilized for the delivery of all CTL peptides. ...
Cytotoxic T-lymphocytes (CTLs) are central for eliciting protective immunity against malignancies and infectious diseases. Here, for the first time, partially oxidized acetalated dextran nanoparticles (Ox-AcDEX NPs) with an average diameter of 100 nm are fabricated as a general platform for vaccine delivery. To develop effective anticancer vaccines, Ox-AcDEX NPs are conjugated with a representative CTL peptide epitope (CTLp) from human mucin-1 (MUC1) with the sequence of TSAPDTRPAP (referred to as Mp1) and an immune-enhancing adjuvant R837 (referred to as R) via imine bond formation affording AcDEX-(imine)-Mp1-R NPs. Administration of AcDEX-(imine)-Mp1-R NPs results in robust and long-lasting anti-MUC1 CTL immune responses, which provides mice with superior protection from the tumor. To verify its universality, this nanoplatform is also exploited to deliver epitopes from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to prevent coronavirus disease 2019 (COVID-19). By conjugating Ox-AcDEX NPs with the potential CTL epitope of SARS-CoV-2 (referred to as Sp) and R837, AcDEX-(imine)-Sp-R NPs are fabricated for anti-SARS-CoV-2 vaccine candidates. Several epitopes potentially contributing to the induction of potent and protective anti-SARS-CoV-2 CTL responses are examined and discussed. Collectively, these findings shed light on the universal use of Ox-AcDEX NPs to deliver both tumor-associated and virus-associated epitopes.
... Aside from delivering small therapeutic molecules, MSNs allow the effective delivery of proteins [153] or DNA strands [154] into bone cancer cells. There is a type of nucleic acids, small interfering RNA (siRNA), that triggers the knockdown of specific and relevant proteins, which makes them useful for the treatment of various diseases [155]. ...
Bone diseases, such as bone cancer, bone infection and osteoporosis, constitute a major issue for modern societies as a consequence of their progressive ageing. Even though these pathologies can be currently treated in the clinic, some of those treatments present drawbacks that may lead to severe complications. For instance, chemotherapy lacks great tumor tissue selectivity, affecting healthy and diseased tissues. In addition, the inappropriate use of antimicrobials is leading to the appearance of drug-resistant bacteria and persistent biofilms, rendering current antibiotics useless. Furthermore, current antiosteoporotic treatments present many side effects as a consequence of their poor bioavailability and the need to use higher doses. In view of the existing evidence, the encapsulation and selective delivery to the diseased tissues of the different therapeutic compounds seem highly convenient. In this sense, silica-based mesoporous nanoparticles offer great loading capacity within their pores, the possibility of modifying the surface to target the particles to the malignant areas and great biocompatibility. This manuscript is intended to be a comprehensive review of the available literature on complex bone diseases treated with silica-based mesoporous nanoparticles—the further development of which and eventual translation into the clinic could bring significant benefits for our future society.
... In order to control the protein release at specific environment (e.g., acidic pH and glucose) or avoid the loss of biomolecules over time, those proteins could be modified on the surface with specific linkage. [138][139][140] To an extent, the highly sensitive proteins could also maintain their bioactivity. For example, Lin and co-workers synthesized the MSN-based nanocarriers to allow efficient intracellular protein delivery. ...
Protein/antibody therapeutics have exhibited the advantages of high specificity and activity even at an extremely low concentration compared to small molecule drugs. However, they are accompanied by unfavorable physicochemical properties such as fragile tertiary structure, large molecular size, and poor penetration of the membrane, and thus the clinical use of protein drugs is hindered by inefficient delivery of proteins into the host cells. To overcome the challenges associated with protein therapeutics and enhance their biopharmaceutical applications, various protein‐loaded nanocarriers with desired functions, such as lipid nanocapsules, polymeric nanoparticles, inorganic nanoparticles, and peptides, are developed. In this review, the different strategies for intracellular delivery of proteins are comprehensively summarized. Their designed routes, mechanisms of action, and potential therapeutics in live cells or in vivo are discussed in detail. Furthermore, the perspective on the new generation of delivery systems toward the emerging area of protein‐based therapeutics is presented as well. Intracellular protein delivery is a powerful tool for a wide array of therapeutic purposes. Here, various nanoparticle‐based systems for intracellular delivery of proteins are comprehensively summarized. Their designed routes, action mechanisms, and potential therapeutics are discussed in detail. Furthermore, the perspective of new generation delivery systems toward the emerging area of protein‐based therapeutics is presented.
... Due to its acid lability, imine bond formed between primary amine and aldehyde is widely used to construct pH responsive delivery system [89,90]. For example, Han et al. synthesized an aldehyde-functionalized MSN (MSN-aldehyde), which could conveniently and efficiently conjugate with model proteins via imine bonds [91]. To track the protein release in the acidic lysosome, the MSN was labeled with lysosome activatable rhodamine-lactams. ...
Mesoporous silica nanoparticles (MSN) have attracted a lot of attention during the past decade which is attributable to their versatile and high loading capacity, easy surface functionalization, excellent biocompatibility, and great physicochemical and thermal stability. In this review, we discuss the factors affecting the loading of protein into MSN and general strategies for targeted delivery and controlled release of proteins with MSN. Additionally, we also give an outlook for the remaining challenges in the clinical translation of protein-loaded MSNs.
... The pH within the lysosomes also can be a considerable challenge when designing a smart MSN based carrier. In one experiment using aldehyde-displaying MSN materials and pH sensitive cleavable imine bonds among loaded proteins and aldehyde groups, researchers were successfully able to deliver proteins into three different cancerous cells including HeLa, HepG2, and L929 [175]. ...
... The eGFP allowed for tracking of the MSN-aldehyde particle in order to evaluate whether or not this system proved useful in this endeavor. Host cells experienced autophagy (self-destruction via delivery of cytoplasmic contents into lysosomes), indicating that the arginase was successfully translocated from lysosomes and retained its enzymatic activity [67]. ...
Protein therapeutics are promising candidates for disease treatment due to their high specificity and minimal adverse side effects; however, targeted protein delivery to specific sites has proven challenging. Mesoporous silica nanoparticles (MSN) have demonstrated to be ideal candidates for this application, given their high loading capacity, biocompatibility, and ability to protect host molecules from degradation. These materials exhibit tunable pore sizes, shapes and volumes, and surfaces which can be easily functionalized. This serves to control the movement of molecules in and out of the pores, thus entrapping guest molecules until a specific stimulus triggers release. In this review, we will cover the benefits of using MSN as protein therapeutic carriers, demonstrating that there is great diversity in the ways MSN can be used to service proteins. Methods for controlling the physical dimensions of pores via synthetic conditions, applications of therapeutic protein loaded MSN materials in cancer therapies, delivering protein loaded MSN materials to plant cells using biolistic methods, and common stimuli-responsive functionalities will be discussed. New and exciting strategies for controlled release and manipulation of proteins are also covered in this review. While research in this area has advanced substantially, we conclude this review with future challenges to be tackled by the scientific community.
... Wu et al. prepared aldehyde-displaying MSNs for cytosolic delivery of proteins into mammalian cells, such as HepG2, HeLa and L929 cells. The results indicated that the MSN-aldehyde nanocomposites could internalize into lysosomes and the model proteins (arginase and green fluorescent protein) were released due to the lysosomal acidity trigger [22]. However, most of studies demonstrated that proteins only adsorbed on the surface of MSNs owing to the small mesopore size, resulting in the limited protein loading and delivery. ...
We developed a potential pH-responsive protein drug delivery system based on aldehyde-functionalized dendritic mesoporous silica nanoparticles (DMSNs-CHO) as nanocarriers. The structure, protein drug loading and release behavior, in vitro cytotoxicity and cell uptake of the DMSNs-CHO nanoparticles were investigated. The results showed that the uniform DMSNs-CHO nanoparticles had an average particle size of 174 ± 17 nm and a mesopore size of 7.7 nm. Using bovine serum albumin (BSA) as a model protein drug, BSA could be loaded into DMSNs-CHO nanoparticles owing to the formation of imine bonds between aldehyde groups and primary amines of BSA molecules. BSA loading capacity was about 136 μg/mg, and BSA release from DMSNs-CHO nanocarriers was dependent on pH environment. Furthermore, the DMSNs-CHO nanoparticles had no cytotoxicity and could be efficiently taken up by cells. Therefore, the DMSNs-CHO nanoparticles would be promising as nanocarriers for pH-responsive delivery of protein drugs.
... MSNs functionalized with hydrophobic or acid labile moieties were recently employed to transport proteins into cells [37]. Wu et al. prepared aldehyde-displaying silica nanoparticles (MSN-aldehyde) containing lysosome activatable rhodamine-lactams for controlled protein delivery via lysosomal acidity-triggered release [38]. The MSN-aldehyde nanocomposites were sitespecifically embodied into lysosomes of HepG2, HeLa and L929 cells where the loaded protein cargoes, including arginase and green fluorescent protein, were released through lysosomal acidity-mediated hydrolysis of the imine cross-linkages. ...
... Adapted with permission from Ref. [118]. TMC-based PEC nanocarriers R-GAL Intracellular [33] polyaspartamide nanocapsules BSA Intracellular: NIH-3T3 [14] single-protein nanocapsules EGFP, HRP, BSA, SOD and CAS Intracellular [34] triple-enzyme nanocomplex alcohol oxidase and catalase Serum [35] aldehyde-displaying silica nanoparticles Arginase, GFP Intracellular: HepG2, HeLa and L929 [38] PAAD/PGA hydrogels insulin Serum [43] multi-ion-crosslinked NPs insulin Serum [44] PLA-PEG NP insulin Serum [45] Redox Glucose GOx contained hydrogels insulin [69] acid-degradable polymeric network insulin Serum [70] enzyme nanocapsuleintegrated pH-responsive microgels insulin Serum [71] ConA contained hydrogels insulin [77] hydrogels based on dextran methacrylate derivative and ConA insulin [79] Stimulus Nanomaterial Model protein/peptide ...
Protein therapeutics have emerged as a significant role in treatment of a broad spectrum of diseases, including cancer, metabolic disorders and autoimmune diseases. The efficacy of protein therapeutics, however, is limited by their instability, immunogenicity and short half-life. In order to overcome these barriers, tremendous efforts have recently been made in developing controlled protein delivery systems. Stimuli-triggered release is an appealing and promising approach for protein delivery and has made protein delivery with both spatiotemporal- and dosage-controlled manners possible. This review surveys recent advances in controlled protein delivery of proteins or peptides using stimuli-responsive nanomaterials. Strategies utilizing both physiological and external stimuli are introduced and discussed.
