Photocrosslinked Bioreducible Polymeric Nanoparticles for Enhanced Systemic siRNA Delivery as Cancer Therapy

Clinical translation of polymer-based nanocarriers for systemic delivery of RNA has been limited due to poor colloidal stability in the blood stream and intracellular delivery of the RNA to the cytosol. To address these limitations, this study reports a new strategy incorporating photocrosslinking of bioreducible nanoparticles for improved stability extracellularly and rapid release of RNA intracellularly. In this design, the polymeric nanocarriers contain ester bonds for hydrolytic degradation and disulfide bonds for environmentally triggered small interfering RNA (siRNA) release in the cytosol. These photocrosslinked bioreducible nanoparticles (XbNPs) have a shielded surface charge, reduced adsorption of serum proteins, and enable superior siRNA-mediated knockdown in both glioma and melanoma cells in high-serum conditions compared to non-crosslinked formulations. Mechanistically, XbNPs promote cellular uptake and the presence of secondary and tertiary amines enables efficient endosomal escape. Following systemic administration, XbNPs facilitate targeting of cancer cells and tissue-mediated siRNA delivery beyond the liver, unlike conventional nanoparticle-based delivery. These attributes of XbNPs facilitate robust siRNA-mediated knockdown in vivo in melanoma tumors colonized in the lungs following systemic administration. Thus, biodegradable polymeric nanoparticles, via photocrosslinking, demonstrate extended colloidal stability and efficient delivery of RNA therapeutics under physiological conditions, and thereby potentially advance systemic delivery technologies for nucleic acid-based therapeutics.     

A Bio‐Inspired Rod‐Shaped Nanoplatform for Strongly Infecting Tumor Cells and Enhancing the Delivery Efficiency of Anticancer Drugs

The rapid clearance of circulating nanocarriers in blood during systemic drug delivery remains a challenging hurdle in cancer chemotherapy. Here, inspired by the unique features of bacterial pathogens, an original biodegradable polymer micellar system with a rod‐like shape similar to the morphology of bacterial pathogens is developed. These novel nanocarriers have excellent features such as a great capacity of overcoming the rapid clearance of reticuloendothelial system (RES) with long blood circulation, high cellular internalization, and enhanced therapeutic efficacy against cancers. In vivo pharmacokinetic studies in mice reveal that the rod‐like micelles of ≈40 nm in diameter and 600 nm in length possess a minimal uptake by the RES and excellent blood circulation half‐lives (t_1/2β = 24.23 ± 2.87 h) for carrying doxorubicin in contrast to spheres (t_1/2β = 8.39 ± 0.53 h). The antitumor activity of the rod‐shaped micelles in Balb/c mice bearing H22 tumor xenograft models reveals that they are promptly internalized by tumor cells, resulting in their superior potency and efficacy against artificial solid tumors. These findings suggest that the bio‐inspired nanocarriers as an emerging drug delivery platform may have considerable benefits for enhancing the delivery efficiency of anticancer drugs and in turn enhancing cancer therapy in future clinical applications.     

Cationic Polymer Modified Mesoporous Silica Nanoparticles for Targeted siRNA Delivery to HER2+ Breast Cancer

In vivo delivery of siRNAs designed to inhibit genes important in cancer and other diseases continues to be an important biomedical goal. A new nanoparticle construct that is engineered for efficient delivery of siRNA to tumors is now described. The construct comprises a 47‐nm mesoporous silica nanoparticle core coated with a crosslinked polyethyleneimine–polyethyleneglycol copolymer, carrying siRNA against the human epidermal growth factor receptor type 2 (HER2) oncogene, and coupled to the anti‐HER2 monoclonal antibody (trastuzumab). The construct is engineered to increase siRNA blood half‐life, enhance tumor‐specific cellular uptake, and maximize siRNA knockdown efficacy. The optimized anti‐HER2 nanoparticles produce apoptotic death in HER2 positive (HER2⁺) breast cancer cells grown in vitro, but not in HER2 negative (HER2^?) cells. One dose of the siHER2–nanoparticles reduces HER2 protein levels by 60% in trastuzumab‐resistant HCC1954 xenografts. Administration of multiple intravenous doses over 3 weeks significantly inhibits tumor growth (p < 0.004). The siHER2‐nanoparticles have an excellent safety profile in terms of blood compatibility and low cytokine induction, when exposed to human peripheral blood mononuclear cells. The construct can be produced with high batch‐to‐batch reproducibility and the production methods are suitable for large‐scale production. These results suggest that this siHER2‐nanoparticle is ready for clinical evaluation.     

Lipid Nanoparticles for Broad-Spectrum Nucleic Acid Delivery

Lipid nanoparticles (LNPs) are the most advanced nonviral modality for nucleic acid (NA) delivery, and have recently gained enormous attention in the fields of RNA therapeutics and vaccine development. Here, ionizable adamantane-based lipidoids named XMaNs, which circumvent the usual need for laborious optimization of LNP components for highly diverse types of NAs, are described. The non-toxic XMaN6 lipidoid is highly versatile in entrapment and delivery of siRNA, mRNA, plasmid DNA, and a cyclic dinucleotide. XMaN6-based LNPs efficiently deliver: 1) siRNA into human primary hepatocytes and cell lines that are hard-to-transfect; 2) mRNA into mouse liver; 3) plasmid DNA; 4) 2′,3′-cGAMP into cells and activated the cGAS-STING pathway three orders of magnitude more efficiently than 2′,3′-cGAMP alone. To our knowledge, such universality in delivering different NA types has not been previously described and can accelerate translation of LNPs into the clinic.     

mRNA-Loaded Lipid-Like Nanoparticles for Liver Base Editing Via the Optimization of Central Composite Design

Messenger RNA (mRNA) has come into the spotlight due to its potential for addressing a staggering number of diseases, while the lack of effective and safe carriers for in vivo delivery significantly limits its clinical application. Herein, the potential of lipid-like nanoparticles (LLNs) containing three new cholesterol derivatives to achieve the liver targeting delivery of mRNA is investigated. The central composite design (CCD) is used to tailor the formulation of LLNs through in vivo optimization of the molar ratios of these cholesterol derivatives required for liver targeting. The optimized LLNs (O-LLNs) are able to systemically deliver mRNA to the liver of mice with a synergistic action of prolonged systemic circulation, increased liver targeting, and enhanced hepatocyte uptake. The O-LLNs outperformed DLin-MC3-DMA (MC3) in functional delivery of Cre-recombinase (Cre) and human erythropoietin (hEPO) mRNA. Successful delivery of cytidine base editor mRNA (CBE mRNA) and sgRNA by O-LLNs achieved more than 8% correction rates in a liver-related metabolism disorder, phenylketonuria (PKU). In conclusion, the general method above can accelerate in vivo screening and optimization of multicomponent nanoparticle formulations, and the optimized ones demonstrate great potential as delivery vehicles for targeted gene therapy in specific tissues.     

A Fabricated siRNA Nanoparticle for Ultralong Gene Silencing In Vivo

Persistent gene silencing is crucially required for the successful therapeutics of short interfering RNA (siRNA). Here, a nanoparticle‐based delivery system is presented which assembles by layering siRNAs between protease degradable polypeptides to extend the therapeutic window. These tightly packed nanoparticles are efficiently taken up by cells by endocytosis, and the fabricated siRNAs are gradually released following intracellular degradation of the polypeptide layers. During cell division, the particles are distributed to the daughter cells. Due to the slow degradation through the multiple layers, the particles continuously release siRNA in all cells. Using this controlled release construct, the in vivo gene silencing effect of siRNA is consistent for an ultralong period of time (>3 weeks) with only a single treatment.     

Polycatechol Mediated Small Interfering RNA Delivery for the Treatment of Ulcerative Colitis

Small interfering RNA (siRNA)-based therapeutics has high potency and specificity in silencing target genes for the treatment of various diseases; however, the design of efficient and safe carriers for siRNA delivery remains grand challenges. In this study, a family of cationic polycatechols are designed and synthesized using different direct polymerization methods for siRNA delivery in vitro and in vivo. It is observed that the introduction of multiple catechol moieties into cationic polymers could enhance their siRNA binding capability, thus greatly improving the biological stability, cell internalization, and gene silencing efficiency of their complexes. The flexibility of the backbone in polycatechols is also found to influence the whole siRNA delivery process. After screening, the lead cationic polycatechol P1 with a 50% catechol molar ratio could efficiently deliver siRNAs into different cell lines and downregulate various target genes even in the presence of serum proteins. Besides, P1 is also able to successfully silence tumor necrosis factor-α in macrophages in vitro and in vivo, and efficiently mitigate the symptoms without causing adverse effects in a dextran sodium sulfate-induced ulcerative colitis model. The results demonstrate that those polycatechols could be developed as a promising class of siRNA delivery systems for gene therapy.     

Biodegradable Dextran Nanogels for RNA Interference: Focusing on Endosomal Escape and Intracellular siRNA Delivery

The successful therapeutic application of small interfering RNA (siRNA) largely relies on the development of safe and effective delivery systems that are able to guide the siRNA therapeutics to the cytoplasm of the target cell. In this report, biodegradable cationic dextran nanogels are engineered by inverse emulsion photopolymerization and their potential as siRNA carriers is evaluated. The nanogels are able to entrap siRNA with a high loading capacity, based on electrostatic interaction. Confocal microscopy and flow cytometry analysis reveal that large amounts of siRNA‐loaded nanogels can be internalized by HuH‐7 human hepatoma cells without significant cytotoxicity. Following their cellular uptake, it is found that the nanogels are mainly trafficked towards the endolysosomes. The influence of two different strategies to enhance endosomal escape on the extent of gene silencing is investigated. It is found that both the application of photochemical internalization (PCI) and the use of an influenza‐derived fusogenic peptide (diINF‐7) can significantly improve the silencing efficiency of siRNA‐loaded nanogels. Furthermore, it is shown that an efficient gene silencing requires the degradation of the nanogels. As the degradation kinetics of the nanogels can easily be tailored, these particles show potential for intracellular controlled release of short interfering RNA.     

Nano‐Self‐Assembly of Nucleic Acids Capable of Transfection without a Gene Carrier

Nonviral gene carriers based on electrostatic interaction, encapsulation, or absorption require a large amount of polymer carrier to achieve reasonable transfection efficiencies. With cationic nanoparticles, for example, genes interact only with the surface of the nanoparticles, resulting in a low surface area to volume ratio (SA/V = 3/r). A large volume of carrier, therefore, is required to deliver a small copy number of genes. In this study, it is demonstrated that a nano‐self‐assembly of nucleic acids transfects itself into cells spontaneously, without the need for a gene carrier. The cellular uptake of this nanoassembly occurs through a number of endocytosis mechanisms. Once within the cell, the nanoassembly can escape endolysosomal vesicles and facilitate gene transfection. This nano‐self‐assembly consisting of zinc and plasmid DNA or siRNA, termed the Zn/DNA or Zn/siRNA nanocluster, is formed through the binding of Zn²⁺ ions to the phosphate groups of nucleic acids. The method described in this paper represents a new platform for carrier‐free gene delivery that can be used to deliver any plasmid DNA or siRNA without the requirement for a specific modification in the nucleic acids or complicated steps to prepare dense particles.     

Optimizing the Size of Micellar Nanoparticles for Efficient siRNA Delivery

Delivery of small interfering RNA (siRNA) by nanocarriers has shown promising therapeutic potential in cancer therapy. However, poor understanding of the correlation between the physicochemical properties of nanocarriers and their interactions with biological systems has significantly hindered its anticancer efficacy. Herein, in order to identify the optimal size of nanocarriers for siRNA delivery, different sized cationic micellar nanoparticles (MNPs) (40, 90, 130, and 180 nm) are developed that exhibit similar siRNA binding efficacies, shapes, surface charges, and surface chemistries (PEGylation) to ensure size is the only variable. Size‐dependent biological effects are carefully and comprehensively evaluated through both in vitro and in vivo experiments. Among these nanocarriers, the 90 nm MNPs show the optimal balance of prolonged circulation and cellular uptake by tumor cells, which result in the highest retention in tumor cells. In contrast, larger MNPs are rapidly cleared from the circulation and smaller MNPs are inefficiently taken up by tumor cells. Accordingly, 90 nm MNPs carrying polo‐like kinase 1 (Plk1)‐specific siRNA (siPlk1) show superior antitumor efficacy, indicating that 90 nm could either be the optimal size for systemic delivery of siRNA or close to it. Our findings provide valuable information for rationally designing nanocarriers for siRNA‐based cancer therapy in the future.     

IL4‐Receptor‐Targeted Dual Antitumoral Apoptotic Peptide—siRNA Conjugate Lipoplexes

Targeted delivery remains the major limitation in the development of small interfering RNA (siRNA) therapeutics. The successful siRNA multistep delivery requires precise carriers of substantial complexity. To achieve this, a monodisperse carrier is presented, synthesized by solid‐phase supported chemistry. The sequence‐defined assembly contains two oleic acids attached to a cationizable oligoaminoamide backbone in T‐shape configuration, and a terminal azide functionality for coupling to the atherosclerotic plaque‐specific peptide‐1 (AP‐1) as the cell targeting ligand for interleukin‐4 receptor (IL‐4R) which is overexpressed in a variety of solid cancers. For combined cytosolic delivery with siRNA, different apoptotic peptides (KLK, BAK, and BAD) are covalently conjugated via bioreversible disulfide linkage to the 5′‐end of the siRNA sense strand. siRNA‐KLK conjugates provide the highest antitumoral potency. The optimized targeted carrier is complexed with dual antitumoral siEG5‐KLK conjugates. The functionality of each subdomain is individually confirmed. The lipo‐oligomer confers stable assembly of siRNA conjugates into spherical 150–250 nm sized nanoparticles. Click‐shielding with dibenzocyclootyne‐PEG‐AP‐1 (DBCO‐PEG‐AP‐1) mediates an IL‐4R‐specific cell targeting and gene silencing in tumor cells. Most importantly, formulation of the siEG5‐KLK conjugate displays enhanced apoptotic tumor cell killing due to the combined effect of mitotic arrest by EG5 gene silencing and mitochondrial membrane disruption by KLK.     

Exploring and Analyzing the Systemic Delivery Barriers for Nanoparticles

Most nanomedicines require efficient in vivo delivery to elicit meaningful diagnostic and therapeutic effects. However, en route to their intended tissues, systemically administered nanoparticles often encounter delivery barriers. To describe these barriers, the term “nanoparticle blood removal pathways” (NBRP) is proposed, which summarizes the interactions between nanoparticles and the body's various cell-dependent and cell-independent blood clearance mechanisms. Nanoparticle design and biological modulation strategies are reviewed to mitigate nanoparticle-NBRP interactions. As these interactions affect nanoparticle delivery, the preclinical literature from 2011–2021 is studied, and the nanoparticle blood circulation and organ biodistribution data are analyzed. The findings reveal that nanoparticle surface chemistry affects the in vivo behavior more than other nanoparticle design parameters. Combinatory biological-PEG surface modification improves the blood area under the curve by ≈418%, with a decrease in liver accumulation of up to 47%. A greater understanding of nanoparticle-NBRP interactions and associated delivery trends will provide new nanoparticle design and biological modulation strategies for safer, more effective, and more efficient nanomedicines.     

Tumor‐Microenvironment‐Adaptive Nanoparticles Codeliver Paclitaxel and siRNA to Inhibit Growth and Lung Metastasis of Breast Cancer

Prolonged circulation, specific and effective uptake by tumor cells, and rapid intracellular drug release are three main factors for the drug delivery systems to win the battle against metastatic breast cancer. In this work, a tumor microenvironment‐adaptive nanoparticle co‐loading paclitaxel (PTX) and the anti‐metastasis siRNA targeting Twist is prepared. The nanoparticle consists of a pH‐sensitive core, a cationic shell, and a matrix metalloproteinase (MMP)‐cleavable polyethylene glycol (PEG) corona conjugated via a peptide linker. PEG will be cut away by MMPs at the tumor site, which endows the nanoparticle with smaller particle size and higher positive charge, leading to more efficient cellular uptake in tumor cells and higher intra‐tumor accumulation of both PTX and siRNA in the 4T1 tumor‐bearing mice models compared to the nanoparticles with irremovable PEG. In addition, acid‐triggered drug release in endo/lysosomes is achieved through the pH‐sensitive core. As a result, the MMP/pH dual‐sensitive nanoparticles significantly inhibit tumor growth and pulmonary metastasis. Therefore, this tumor‐microenvironment‐adaptive nanoparticle can be a promising codelivery vector for effective therapy of metastatic breast cancer due to simultaneously satisfying the requirements of long circulating time, efficient tumor cell targeting, and fast intracellular drug release.     

Bioengineered Extracellular Membranous Nanovesicles for Efficient Small‐Interfering RNA Delivery: Versatile Platforms for Stem Cell Engineering and In Vivo Delivery

Naturally derived nanovesicles secreted from various cell types and found in body fluids can provide effective platforms for the delivery of various cargoes because of their intrinsic ability to be internalized for intercellular signal transmission and membrane recycling. In this study, the versatility of bioengineered extracellular membranous nanovesicles as potent carriers of small‐interfering RNAs (siRNAs) for stem cell engineering and in vivo delivery has been explored. Here, exosomes have been engineered, one of the cell‐derived vesicle types, to overexpress exosomal proteins fused with cell‐adhesion or cell‐penetrating peptides for enhanced intracellular gene transfer. To devise a more effective delivery system with potential for mass production, a new siRNA delivery system has also been developed by artificially inducing the outward budding of plasma membrane nanovesicles. Those nanovesicles have been engineered by overexpressing E‐cadherin to facilitate siRNA delivery to human stem cells with resistance to intracellular gene transfer. Both types of engineered nanovesicles deliver siRNAs to human stem cells for lineage specification with negligible cytotoxicity. The nanovesicles are efficient in delivering siRNA in vivo, suggesting feasibility for gene therapy. Cell‐derived, bioengineered nanovesicles used for siRNA delivery can provide functional platforms enabling effective stem cell therapeutics and in vivo gene therapy.     

Targeted Ultrasound-Mediated Delivery of Nanoparticles: On the Development of a New HIFU-Based Therapy and Imaging Device

Ultrasound-mediated delivery (USMD) is an active research topic, as researchers develop applications for therapeutic ultrasound in addition to thermal ablation. In USMD, ultrasound is used in conjunction with microbubbles and drugs, nanoparticles, siRNA, pDNA, stem cells, etc., to facilitate their cellular delivery and uptake using pressure and temperature-mediated mechanisms to bring about a desired therapeutic effect. To investigate the potential of targeted USMD of nanoparticles, pDNA, and stem cells for cardiovascular and other applications, a general-purpose preclinical research tool, therapy imaging probe system (TIPS) was designed. It consists of a wideband annular array, a small-animal acoustic coupler, a motorized positioning system, integrated control software for ultrasound image-guided treatment planning and execution, and triggering electronics that allow ECG and respiration-gated ultrasound exposures. TIPS was then used to enhance delivery of nanoparticles into the murine myocardium and heart vessel walls to demonstrate the feasibility of the technology, pave the way for additional basic research in cardiovascular USMD, and begin to explore the requirements that USMD devices will have to meet to be useful in a clinical setting.      

Binary Targeting of siRNA to Hematologic Cancer Cells In Vivo Using Layer‐by‐Layer Nanoparticles

Using siRNA therapeutics to treat hematologic malignancies has been unsuccessful because blood cancer cells exhibit remarkable resistance to standard transfection methods. Herein, the successful delivery of siRNA therapeutics with a dual‐targeted, layer‐by‐layer nanoparticle (LbL‐NP) is reported. The LbL‐NP protects siRNA from nucleases in the bloodstream by embedding it within polyelectrolyte layers that coat a polymeric core. The outermost layer consists of hyaluronic acid (a CD44‐ligand) covalently conjugated to CD20 antibodies. The CD20/CD44 dual‐targeting outer layer provides precise binding to blood cancer cells, followed by receptor‐mediated endocytosis of the LbL‐NP. This siRNA delivery platform is used to silence B‐cell lymphoma 2 (BCL‐2), a pro‐survival protein, in vitro and in vivo. The dual‐targeting approach significantly enhances internalization of BCL‐2 siRNA in lymphoma and leukemia cells, which leads to significant downregulation of BCL‐2 expression. Systemic administration of the dual‐targeted, siRNA‐loaded nanoparticle induces apoptosis and hampers proliferation of blood cancer cells, both in cell culture and in orthotopic non‐Hodgkin's lymphoma animal models. These results provide the basis for approaches to targeting blood‐borne cancers and other diseases and suggest that LbL nanoassemblies are a promising approach for delivering therapeutic siRNA to hematopoetic cell types that are known to evade transfection by other means.     

Simple and Efficient Targeted Intracellular Protein Delivery with Self‐Assembled Nanovehicles for Effective Cancer Therapy

Protein therapy offers promising prospects for the treatment of various important diseases, thus it is highly desirable to develop a robust carrier that can deliver active proteins into cells. The development of a novel protein delivery platform based on the self‐assembly of multiarmed amphiphilic cyclodextrins (CDEH) is reported. CDEH can self‐assemble into nanoparticles in aqueous solution and achieve superior encapsulation of protein (loading capacity > 30% w/w) simply by mixing with protein solution without introducing any subsequent cumbersome steps that may inactivate proteins. More importantly, CDEH nanovehicles can be easily further modified with various targeting groups based on host–guest complexation. Using saporin as a therapeutic protein, AS1411‐aptamer‐modified CDEH nanovehicles can preferentially accumulate in tumors and efficiently inhibit tumor growth in a MDA‐MB‐231 xenograft mouse model. Moreover, folate‐targeted CDEH nanovehicles can also deliver Cas9 protein and Plk1‐targeting sgRNA into Hela cells, leading to 47.1% gene deletion and 64.1% Plk1 protein reduction in HeLa tumor tissue, thereby effectively suppressing the tumor progression. All these results indicate the potential of targeted CDEH nanovehicles in intracellular protein delivery for improving protein therapeutics.     

A Fluorinated Bola‐Amphiphilic Dendrimer for On‐Demand Delivery of siRNA,via Specific Response to Reactive Oxygen Species

Functional materials capable of responding to stimuli intrinsic to diseases are extremely important for specific drug delivery at the disease site. However, developing on‐demand stimulus‐responsive vectors for targeted delivery is highly challenging. Here, a stimulus‐responsive fluorinated bola‐amphiphilic dendrimer is reported for on‐demand delivery of small interfering RNA (siRNA) in response to the characteristic high level of reactive oxygen species (ROS) in cancer cells. This dendrimer bears a ROS‐sensitive thioacetal in the hydrophobic core and positively charged poly(amidoamine) dendrons at the terminals, capable of interacting and compacting the negatively charged siRNA into nanoparticles to protect the siRNA and promote cellular uptake. The ROS‐sensitive feature of this dendrimer boosts specific and efficient disassembly of the siRNA/vector complexes in ROS‐rich cancer cells for effective siRNA delivery and gene silencing. Moreover, the fluorine tags in the vector enable ¹⁹F‐NMR analysis of the ROS‐responsive delivery process. In addition, this ingenious and distinct bola‐amphiphilic dendrimer is also able to combine the advantageous delivery features of both lipid and dendrimer vectors. Therefore, it represents an innovative on‐demand stimulus‐responsive delivery platform.     

Biocompatible,Uniform, and Redispersible Mesoporous Silica Nanoparticles for Cancer‐Targeted Drug Delivery In Vivo

Engineering multifunctional nanocarriers for targeted drug delivery shows promising potentials to revolutionize the cancer chemotherapy. Simple methods to optimize physicochemical characteristics and surface composition of the drug nanocarriers need to be developed in order to tackle major challenges for smooth translation of suitable nanocarriers to clinical applications. Here, rational development and utilization of multifunctional mesoporous silica nanoparticles (MSNPs) for targeting MDA‐MB‐231 xenograft model breast cancer in vivo are reported. Uniform and redispersible poly(ethylene glycol)‐incorporated MSNPs with three different sizes (48, 72, 100 nm) are synthesized. They are then functionalized with amino‐β‐cyclodextrin bridged by cleavable disulfide bonds, where amino‐β‐cyclodextrin blocks drugs inside the mesopores. The incorporation of active folate targeting ligand onto 48 nm of multifunctional MSNPs (PEG‐MSNPs48‐CD‐PEG‐FA) leads to improved and selective uptake of the nanoparticles into tumor. Targeted drug delivery capability of PEG‐MSNPs48‐CD‐PEG‐FA is demonstrated by significant inhibition of the tumor growth in mice treated with doxorubicin‐loaded nanoparticles, where doxorubicin is released triggered by intracellular acidic pH and glutathione. Doxorubicin‐loaded PEG‐MSNPs48‐CD‐PEG‐FA exhibits better in vivo therapeutic efficacy as compared with free doxorubicin and non‐targeted nanoparticles. Current study presents successful utilization of multifunctional MSNP‐based drug nanocarriers for targeted cancer therapy in vivo.     

High‐Drug‐Loading Mesoporous Silica Nanorods with Reduced Toxicity for Precise Cancer Therapy against Nasopharyngeal Carcinoma

Nanorod‐based drug delivery systems have attracted great interest because of their enhanced cell internalization capacity and improved drug loading property. Herein, novel mesoporous silica nanorods (MSNRs) with different lengths are synthesized and used as nanocarriers to achieve higher drug loading and anticancer activity. As expected, MSNRs‐based drug delivery systems can effectively enhance the loading capacity of drugs and penetrate into tumor cells more rapidly than spherical nanoparticles due to their greater surface area and trans‐membrane transporting rates. Interestingly, these tailored MSNRs also enhance the cellular uptake of doxorubicin (DOX) in cancer cells, thus significantly enhancing its anticancer efficacy for hundreds of times by inducing of cell apoptosis. Internalized MSNRs‐DOX triggers intracellular reactive oxygen species (ROS) overproduction, which subsequently activates p53 and mitogen‐activated protein kinases (MAPKs) pathways to promote cell apoptosis. MSNRs‐DOX nanosystem also shows prolonged blood circulation time in vivo. In addition, MSNRs‐DOX significantly inhibits in vivo tumor growth in nude mice model and effectively reduced its in vivo toxicity. Therefore, this study provides an effective and safe strategy for designing chemotherapeutic agents for precise cancer therapy.