Innovative nebulization delivery of lipid nanoparticle-encapsulated siRNA: a therapeutic advance for Staphylococcus aureus-induced pneumonia.

BACKGROUND: Integrin α5ß1 plays a crucial role in the invasion of nonphagocytic cells by Staphylococcus aureus (S. aureus), thereby facilitating infection development. Lipid nanoparticles (LNPs) serve as an effective vehicle for delivering small interfering ribonucleic acids (siRNA) that represent a method to knockdown integrin α5ß1 in the lungs through nebulization, thereby potentially mitigating the severity of S. aureus pneumonia. The aim of this study was to harness LNP-mediated targeting to precisely knockdown integrin α5ß1, thus effectively addressing S. aureus-induced pneumonia. METHODS: C57 mice (8 week-old females) infected with S. aureus via an intratracheal nebulizing device were utilized for the experiments. The LNPs were synthesized via microfluidic mixing and characterized by their size, polydispersity index, and encapsulation efficiency. Continuous intratracheal nebulization was employed for consistent siRNA administration, with the pulmonary function metrics affirming biosafety. The therapeutic efficacy of LNP-encapsulated siRNAs against pneumonia was assessed through western blotting, bacterial count measurement, quantitative polymerase chain reaction, and histological analyses. RESULTS: LNPs, which have an onion-like structure, retained integrity post-nebulization, ensuring prolonged siRNA stability and in vivo safety. Intratracheal nebulization delivery markedly alleviated the severity of S. aureus-induced pneumonia, as indicated by reduced bacterial load and bolstered immune response, thereby localizing the infection to the lungs and averting systemic dissemination. CONCLUSIONS: Intratracheal nebulization of LNP-encapsulated siRNAs targeting integrin α5ß1 significantly diminished the S. aureus-mediated cellular invasion and disease progression in the lungs, presenting a viable therapeutic approach for respiratory infections.

In Vivo Evaluation of Nose-to-Brain Delivery of Liposomal Donepezil, Memantine, and BACE-1 siRNA for Alzheimer's Disease Therapy.

Our study took an innovative approach by evaluating, in vivo, the efficacy of intranasal (IN) administration of liposomal formulations of donepezil, memantine, and beta-site amyloid precursor protein-cleaving enzyme (BACE-1) siRNA, and their combination as a "triple-drug therapy" in treating Alzheimer's disease (AD). Female APP/PS1 homozygous, transgenic mice were used as an AD model. The spatial short-term memory of the APP/PS1 mice was evaluated by a Y-maze behavioral test. IN-administered formulations demonstrated better short-term memory recovery than oral administration. Triple-drug therapy induced short-term memory recovery and lowered beta-amyloid (Aß) 40 and 42 peptide levels and BACE-1 mRNA expression. Additionally, inflammatory cytokine mRNA expression was downregulated. This innovative approach opens new possibilities for Alzheimer's disease treatment and nose-to-brain delivery.

A novel, non-toxic chitosan modified with lysine to enhance buffer capacity for siRNA delivery.

The present study employed lysine as a modifying agent for chitosan (CS) to synthesise a novel CS derivative (LGCS) intended for siRNA delivery. The successful grafting of lysine to CS was characterized using FT-IR and the introduction of the lysine moiety resulted in improved solubility and buffering capacity of CS. The Zeta potential and size of LGCS/siRNA nanoparticles (NPs) were evaluated using dynamic light scattering (DLS) and the results were verified by transmission electron microscopy (TEM). Evaluation of LGCS's siRNA binding capacity was conducted using a gel retardation assay. The results showed that LGCS could effectively bind to siRNA and form a complex with a hydrated diameter of about 97.2 ± 1.3 nm. Furthermore, cytotoxicity assays conducted on RSC96 cells demonstrated that LGCS exhibited lower toxicity compared to linear polyethyleneimine (PEI) 25k. In vitro, cellular uptake assays also revealed that LGCS displayed excellent transfection efficiency. The results of our study lead us to the conclusion that LGCS holds great promise as a gene delivery vector.

Development of a Lipid-encapsulated TGFßRI-siRNA Drug for Liver Fibrosis Induced by Schistosoma mansoni.

Schistosoma mansoni infection leads to chronic schistosomiasis and severe hepatic fibrosis. We designed a liver-targeted lipid nanoparticle (LNP) carrying siRNA against type I TGF-ß receptor (TGFßRI) mRNA to treat schistosomiasis-induced liver fibrosis in BALB/c mice. Knockdown of TGFßRI by LNP-siTGFßRI reduced LX-2 cell activation in vitro and alleviated liver fibrosis in S. mansoni-infected mice. αSMA and Col1a1 fibrotic markers in the liver tissues of infected mice were significantly suppressed in the treatment groups. In the serum of the LNP-siTGFßRI-treated groups, cytokines IFNγ, IL-1α, IL-6, IL-12, RANTES (CCL5), and TNFα increased, while GM-CSF, IL-2, IL-4, IL-10, IL-13, and KC (CXCL1) decreased compared to the control. Cell proportions were significantly altered in S. mansoni-infected mice, with increased CD56d NK cells and decreased CD19+ B cells and CD4+ T cells compared to naïve mice. Following LNP-siTGFßRI treatment, CD56d NK cells were downregulated, while B and memory Th cell populations were upregulated. The density of fibrotic regions significantly decreased with LNP-siTGFßRI treatment in a dose-dependent manner, and no systemic toxicity was observed in the major organs. This targeted siRNA delivery strategy effectively reduced granulomatous lesions in schistosomiasis-induced liver fibrosis without detectable side effects.

Antitumor Effect of Oleoyl-siRNA against Pancreatic Cancer Using a Portal Vein Infusion Liver-Metastatic Mouse Model.

In this study, we developed an oleoyl-siRNA conjugate in which oleic acid was conjugated at the 5'-end of the sense strand of the siRNA. Furthermore, we examined the effects of RNAi in a mouse model of pancreatic cancer with liver metastasis. The mouse model of pancreatic cancer with liver metastasis was developed by implanting Sui67Luc human pancreatic cancer cells into the portal veins of mice. Sui67Luc cells have high expression of tumor-related genes such as ß-catenin, vascular endothelial growth factor, and programmed cell death ligand-1. All genes were knocked down using siRNA, among which siRNA targeting ß-catenin exhibited the most suitable RNAi effect. Therefore, we investigated the in vitro RNAi effect of oleoyl-siRNA (Ole-siRNA) targeting the ß-catenin gene in Sui67Luc cells and found that it was stronger than that of unmodified siRNA. For in vivo experiments, we investigated the biodistribution, antitumor effect, and change in life expectancy of mice upon systemic administration of Ole-siRNA complexed with Invivofectamine 3.0 (IVF). In terms of biodistribution, the Ole-siRNA/IVF complex likely accumulates in the liver of mice. The antitumor effect of Ole-siRNA in a portal vein infusion liver-metastatic Sui67Luc tumor mouse model was evaluated using an in vivo imaging system. Ole-siRNA had a significant antitumor effect compared with nonmodified siRNA. In addition, mice with metastatic liver Sui67Luc tumors treated with Ole-siRNA showed increased survival. These results suggest that Ole-siRNAs are useful novel RNAi molecules for treating pancreatic cancer and liver metastasis.

A drug delivery system of HIF-1α siRNA nanoparticles loaded by mesenchymal stem cells on choroidal neovascularization.

Aim: To assess mesenchymal stem cells (MSCs) as carriers for HIF-1α siRNA-loaded nanoparticles (NPs) for targeted therapy of experimental choroidal neovascularization (CNV).Materials & methods: A poly (lactic-co-glycolic acid) (PLGA)-core/lipid-shell hybrid NP was designed. The transfection efficacy of MSCs with the hybrid NPs was assessed. Mice were intravenously injected with MSCs after laser photocoagulation and CNV was assessed at 7 days post-injection.Results & conclusion: The transfection efficiency of hybrid NPs into MSCs was 72.7%. HIF-1α mRNA expression in 661w cells co-cultured with MSC-hybrid-siRNA NPs was significantly lower. Intravenous delivery of MSC-hybrid-siRNA NPs greatly reduced CNV area and length. Intravenous injection of MSC-hybrid-siRNA NPs achieved therapeutic efficacy in reducing CNV area. The MSC-mediated homing enabled targeted inhibition of ocular angiogenesis.

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Curdlan-Mediated Syngeneic RNAi against NF-κB in Glial Cells Protects Cerebral Vessels in the TBI Mouse Model.

Traumatic brain injury (TBI) activates the NF-κB pathway in microglia and astrocytes, which secrete pro-inflammatory cytokines that disrupt the blood-brain barrier (BBB). Curdlan derivatives are promising carriers for the delivery of siRNA drugs. Herein, we evaluated the glial cell specificity, siRNA delivery efficiency, and the subsequent phenotypic regulation of glial cells by the Curdlan derivatives in the TBI mouse model. Our in vitro and in vivo studies confirmed that the (1) pAVC4 or CuMAN polymer encapsulating siRNA were internalized by astrocytes and microglia in a receptor-dependent manner; (2) systemic administration of the pAVC4 or CuMAN polymer encapsulating siRNA resulted in significant gene silencing efficiency, altered the phenotypic polarization of glial cells, and regulated the secretion of inflammatory cytokines; (3) this lessened neuroinflammation, ameliorated BBB destruction, and improved vascular recovery. These data suggested that pAVC4 and CuMAN polymers are promising RNA delivery vehicles that can efficiently deliver siRNA to the target cells.

Improving Seed Shattering Resistance in Wild O. alta Rice with Mesoporous Silica Nanoparticle Delivery Systems.

To address food security challenges and climate change, the polyploid wild rice Oryza alta has been explored as a potential crop, although it suffers from seed shattering. We employed mesoporous silica nanoparticles (MSNs) to deliver small interfering RNAs (siRNAs) for targeted gene silencing. Foliar spraying of MSN-siRNA complexes effectively delivered siRNA, resulting in up to 70% gene silencing of the PDS gene and 75% silencing of the transgenic Ruby gene. Additionally, MSN-siRNAs were infiltrated into the panicles of O. alta to target four seed shattering major genes every other day for 2 weeks until heading outdoors. This method silenced all four shattering genes ranging from 10.7% to 49.4% and significantly reduced the formation of the abscission layer between rice grains and pedicels, which enhanced pedicel tensile strength. Our MSN-siRNA system provides a flexible, nonpermanent approach to modifying crop traits, offering a promising tool for sustainable agricultural practices.

Ultrasound-mediated nanobubbles loaded with STAT6 siRNA inhibit TGF-ß1-EMT axis in LUSC cells via overcoming the polarization of M2-TAMs.

M2-like tumor-associated macrophages (M2-TAMs) are closely correlated with metastasis and poor clinical outcomes in lung squamous cell carcinoma (LUSC). Previous studies have demonstrated that STAT6 is an important signaling molecule involved in the polarization of M2-TAMs, EMT is the main way for TAMs to promote tumor progression. However, little attention has been paid to the effect of STAT6 inhibition on LUSC, and it is difficult to achieve an ideal gene silencing effect in immune cells using traditional gene transfection methods. Here, we investigated the optimal concentration of 12-myristic 13-acetate (PMA), lipopolysaccharide (LPS) for the induction of THP-1 into M1-TAMs and M2-TAMs. The expression of pSTAT6 and STAT6 was confirmed in three types of macrophages, and it was demonstrated that pSTAT6 can be used as a specific target of M2-TAMs derived from THP-1. Ultrasound-mediated nanobubble destruction (UMND) is a non-invasive and safe gene delivery technology. We also synthesized PLGA-PEI nanobubbles (NBs) to load and deliver STAT6 small interfering RNA (siRNA) into M2-TAMs via UMND. The results show that the NBs could effectively load with siRNA and had good biocompatibility. We found that UMND enhanced the transfection efficiency of siRNA, as well as the silencing effect of pSTAT6 and the inhibition of M2-TAMs. Simultaneously, when STAT6 siRNA entered M2-TAMs by UMND, proliferation, migration, invasion and EMT in LUSC cells could be inhibited via the transforming growth factor-ß1 (TGF-ß1) pathway. Therefore, our results confirm that UMND is an ideal siRNA delivery strategy, revealing its potential to inhibit M2-TAMs polarization and ultimately treat LUSC.

The siEGFR nanoplexes for the enhanced brain glioma treatment: Endoplasmic reticulum biomimetic strategy to induce homing effect and non-degradable intracellular transport.

The epidermal growth factor receptor (EGFR) plays a pivotal role in tumor progression and is an essential therapeutic target for treating malignant gliomas. Small interfering RNA (siRNA) has the potential to selectively degrade EGFR mRNA, yet its clinical utilization is impeded by various challenges, such as inefficient targeting and limited escape from lysosomes. Our research introduces polyethylene glycol (PEG) and endoplasmic reticulum membrane-coated siEGFR nanoplexes (PEhCv/siEGFR NPs) as an innovative approach to brain glioma therapy by overcoming several obstacles: 1) Tumor-derived endoplasmic reticulum membrane modifications provide a homing effect, facilitating targeted accumulation and cellular uptake; 2) Endoplasmic reticulum membrane proteins mediate a non-degradable "endosome-Golgi-endoplasmic reticulum" transport pathway, circumventing lysosomal degradation. These nanoplexes demonstrated significantly enhanced siEGFR gene silencing in both in vitro and in vivo U87 glioma models. The findings of this study pave the way for the advanced design and effective application of nucleic acid-based therapeutic nanocarriers.

Intestinal probiotic-based nanoparticles for cytotoxic siRNA delivery in immunotherapy against cancer.

Immunogene therapy has emerged as strategy against cancer by introducing immune-stimulating components into gene therapy. However, there is still a need for an ideal platform to achieve both immune stimulation and efficient gene delivery. Lactobacillus reuteri has potential immunomodulatory activity owing to its unique antigenicity, which is potentially relevant to cancer progression. Here, we designed a novel non-viral siRNA vector (DMPLAC) by encapsulating Lactobacillus reuteri lysate in DMP. DMPLAC can promote maturation and activation of immune cells, increase infiltration of APC and cytotoxic T cells in tumor microenvironment, and exhibit tumor suppressive effects. Loading of siRNA targeting Stat3, DMPLAC/siStat3 further inhibits tumor in multiple models. We designed a strategy that combines immune activation with Stat3 silencing, triggering an immune response and tumor killing. This dual-functional design provides a new choice in development of effective immunogene therapy.

Oral bomb effect nanotherapeutics alleviate ulcerative colitis through coordinated anti-inflammatory and pro-resolving strategies.

Background: Ulcerative colitis (UC) is a debilitating chronic inflammatory bowel disease, and current treatments primarily focus on suppressing inflammation with limited efficacy. However, the resolution of inflammation also plays a crucial role in UC prognosis. Combining anti-inflammatory and pro-inflammatory resolution interventions may be a promising approach for treating UC. Materials and methods: The nano-bomb nanoparticles were validated for their ability to load CD98 siRNA (siCD98) and Annexin A1-mimetic peptides (Ac2-26 peptides), as well as release CO2 upon lysosomal escape. Surface modification with hyaluronic acid (HA) was assessed for its capability to target inflammatory tissues and cells. Biocompatibility and biosafety were evaluated through in vitro and in vivo studies. The anti-inflammatory and pro-resolving effects of siCD98@NPs and Ac2-26@NPs, both individually and in combination, were evaluated by measuring ROS production, pro-inflammatory cytokine expression, CD98 gene expression, and macrophage polarization. Results: These nanoparticles could efficiently load siCD98 and Ac2-26 peptides and release CO2 under acidic pH in the endo/lysosome to deliver drugs to the cytoplasm. HA could effectively target the inflammatory tissue and cells, showing good biocompatibility and biosafety both in vitro and in vivo. siCD98@NPs and Ac2-26@NPs showed anti-inflammatory effects by eliminating the over-production of ROS and down-regulating the expression of pro-inflammatory cytokines (TNF-α and IL-1ß) and the CD98 gene; meanwhile, it showed pro-resolving function by inhibiting M0 to pro-inflammatory M1 macrophage conversion, with a more pronounced effect when combined with siCD98 and Ac2-26. The oral administration of chitosan-alginate hydrogel-encapsulated nanoparticles in UC model mice effectively alleviated inflammatory symptoms, reduced the expression of pro-inflammatory cytokines (TNF-α and IL-1ß) and the CD98 gene, restored intestinal barrier function, and promoted M1 to M2 polarization, with a more pronounced effect when combined. Conclusion: By combining anti-inflammatory and pro-resolution interventions, these nanoparticles offer a novel therapeutic approach. This study offered a new approach for combination therapy of UC.

PEGylation Can Effectively Strike a Balance in siRNA Delivery Performances of Guanidinylated Linear Synthetic Polypeptides with Potential Use for Transcriptional Gene Silencing.

The prevailing design philosophy for polymeric vectors delivering siRNA is rooted in the post-transcriptional gene silencing (PTGS) mechanism. Yet, the transcriptional gene silencing (TGS) mechanism offers a potentially more durable silencing effect, which necessitates efficient siRNA delivery into the nucleus. However, it remains a challenge for the polymeric vectors to efficiently deliver siRNA into the nucleus. We have explored guanidinylated cyclic synthetic polypeptides (GCSPs) to enhance the nuclear delivery of siRNA, but an increased cytotoxicity and difficulty in producing the GCSPs on a large scale limit their utility. Herein, we simply prepare PEGylated guanidinylated linear synthetic polypeptides (PGLSPs) exhibiting improved membrane penetration, direct siRNA transport to the nucleus, reduced toxicity, high cellular uptake, and mitigation of protein corona formation. The PEGylation can effectively balance the vector's nuclear delivery capacity with other critical aspects of performances for siRNA delivery. Therefore, the PGLSPs hold promise as TGS-based delivery vectors, offering potential for future therapeutic applications.

Liposomal Formulations of Anti-Alzheimer Drugs and siRNA for Nose-to-Brain Delivery: Design, Safety and Efficacy In Vitro.

ß-site amyloid precursor protein cleaving enzyme (BACE1) represents a key target for Alzheimer's disease (AD) therapy because it is essential for producing the toxic amyloid ß (Aß) peptide that plays a crucial role in the disease's development. BACE1 inhibitors are a promising approach to reducing Aß levels in the brain and preventing AD progression. However, systemic delivery of such inhibitors to the brain demonstrates limited efficacy because of the presence of the blood-brain barrier (BBB). Nose-to-brain (NtB) delivery has the potential to overcome this obstacle. Liposomal drug delivery systems offer several advantages over traditional methods for delivering drugs and nucleic acids from the nose to the brain. The current study aims to prepare, characterize, and evaluate in vitro liposomal forms of donepezil, memantine, BACE-1 siRNA, and their combination for possible treatment of AD via NtB delivery. All the liposomal formulations were prepared using the rotary evaporation method. Their cellular internalization, cytotoxicity, and the suppression of beta-amyloid plaque and other pro-inflammatory cytokine expressions were studied. The Calu-3 Transwell model was used as an in vitro system for mimicking the anatomical and physiological conditions of the nasal epithelium and studying the suitability of the proposed formulations for possible NtB delivery. The investigation results show that liposomes provided the effective intracellular delivery of therapeutics, the potential to overcome tight junctions in BBB, reduced beta-amyloid plaque accumulation and pro-inflammatory cytokine expression, supporting the therapeutic potential of our approach.

Hybrid Liposome-MSN System with Co-Delivering Potential Effective Against Multidrug-Resistant Tumor Targets in Mice Model.

Introduction: RNA interference (RNAi) stands as a widely employed gene interference technology, with small interfering RNA (siRNA) emerging as a promising tool for cancer treatment. However, the inherent limitations of siRNA, such as easy degradation and low bioavailability, hamper its efficacy in cancer therapy. To address these challenges, this study focused on the development of a nanocarrier system (HLM-N@DOX/R) capable of delivering both siRNA and doxorubicin for the treatment of breast cancer. Methods: The study involved a comprehensive investigation into various characteristics of the nanocarrier, including shape, diameter, Fourier transform infrared (FT-IR) spectroscopy, X-ray photoelectron spectroscopy (XPS), encapsulation efficiency, and drug loading. Subsequently, in vitro and in vivo studies were conducted on cytotoxicity, cellular uptake, cellular immunofluorescence, lysosome escape, and mouse tumor models to evaluate the efficacy of the nanocarrier in reversing tumor multidrug resistance and anti-tumor effects. Results: The results showed that HLM-N@DOX/R had a high encapsulation efficiency and drug loading capacity, and exhibited pH/redox dual responsive drug release characteristics. In vitro and in vivo studies showed that HLM-N@DOX/R inhibited the expression of P-gp by 80%, inhibited MDR tumor growth by 71% and eliminated P protein mediated multidrug resistance. Conclusion: In summary, HLM-N holds tremendous potential as an effective and targeted co-delivery system for DOX and P-gp siRNA, offering a promising strategy for overcoming MDR in breast cancer.

Photoreceptor-targeted extracellular vesicles-mediated delivery of Cul7 siRNA for retinal degeneration therapy.

Rationale: Photoreceptor loss is a primary pathological feature of retinal degeneration (RD) with limited treatment strategies. RNA interference (RNAi) has emerged as a promising method of gene therapy in regenerative medicine. However, the transfer of RNAi therapeutics to photoreceptors and the deficiency of effective therapeutic targets are still major challenges in the treatment of RD. Methods: In this study, photoreceptor-derived extracellular vesicles (PEVs) conjugated with photoreceptor-binding peptide MH42 (PEVsMH42) were prepared using the anchoring peptide CP05. Transcriptome sequencing was applied to investigate the potential therapeutic target of RD. We then engineered PEVsMH42 with specific small-interfering RNAs (siRNAs) through electroporation and evaluated their therapeutic efficacy in N-methyl-N-nitrosourea (MNU)-induced RD mice and Pde6ßrd1/rd1 mutant mice. Results: PEVsMH42 were selectively accumulated in photoreceptors after intravitreal injection. Cullin-7 (Cul7) was identified as a novel therapeutic target of RD. Taking advantage of the established PEVsMH42, siRNAs targeting Cul7 (siCul7) were efficiently delivered to photoreceptors and consequently blocked the expression of Cul7. Moreover, suppression of Cul7 effectively protected photoreceptors to alleviate RD both in MNU-induced mouse model and Pde6ßrd1/rd1 mutant mouse model. Mechanistically, PEVsMH42 loaded with siCul7 (PEVsMH42-siCul7)-induced Cul7 downregulation was responsible for preventing Cul7-mediated glutathione peroxidase 4 (Gpx4) ubiquitination and degradation, resulting in the inhibition of photoreceptor ferroptosis. Conclusions: In summary, PEVsMH42-siCul7 attenuate photoreceptor ferroptosis to treat RD by inhibiting Cul7-induced ubiquitination of Gpx4. Our study develops a PEVs-based platform for photoreceptor-targeted delivery and highlights the potential of PEVsMH42-siCul7 as effective therapeutics for RD.

Novel injectable polypeptide nanoparticle encapsulated siRNA targeting TGF-ß1 and COX-2 for localized fat reduction I: Preclinical in vitro and animal models.

BACKGROUND: Obesity and localized fat accumulation continue to drive the demand for minimally invasive body contouring technologies including injectable compounds for local fat reduction. siRNA offers a potential for an injectable to specifically target and silence genes involved in adipogenesis with minimal inflammatory side effects. AIMS: This study evaluates the efficacy of STP705, an injectable containing siRNA encapsulated within histidine-lysine polypeptide (HKP) nanoparticles targeting transforming growth factor ß1 (TGF-ß1) and cyclooxygenase-2 (COX-2), crucial mediators in adipocyte differentiation and fat retention, using in vitro, porcine, and murine models. METHODS: In vitro experiments on mouse preadipocytes and in vivo trials using Diet Induced Obese (DIO) mice and Yucatan minipigs were conducted to assess the gene silencing efficiency, tissue localization, pharmacodynamics, and safety profile of STP705. RESULTS: STP705 effectively reduced the expression of TGF-ß1 and COX-2, with a notable decrease in adipocyte volume and lipid content without adverse systemic effects. In DIO mice, the HKP-siRNA complex demonstrated precise localization to injected adipose tissue, maintaining significant gene silencing, and detectable levels of siRNA for up to 14 days post-administration. Similar results in minipigs showed a significant reduction in subcutaneous adipose tissue thickness. CONCLUSION: The results of these studies support the use of targeted siRNA therapy specifically targeting TGF-ß1 and COX-2, for localized fat reduction, offering a potential minimally invasive alternative to current fat reduction methods.

The advancement of siRNA-based nanomedicine for tumor therapy.

Small interfering RNA (siRNA) has been proved to be able to effectively down-regulate gene expression through the RNAi mechanism. Thus, siRNA-based drugs have become one of the hottest research directions due to their high efficiency and specificity. However, challenges such as instability, off-target effects and immune activation hinder their clinical application. This review explores the mechanisms of siRNA and the challenges in siRNA-based tumor therapy. It highlights the use of various nanomaterials - including lipid nanoparticles, polymeric nanoparticles and inorganic nanoparticles - as carriers for siRNA delivery in different therapeutic modalities. The application strategies of siRNA-based nanomedicine in chemotherapy, phototherapy and immunotherapy are discussed in detail, along with recent clinical advancements. Aiming to provide insights for future research and therapeutic approaches.

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An investigation of nano- and micron-sized carriers based on calcium carbonate and polylactic acid for oral administration of siRNA.

BACKGROUND: Oral delivery of small interfering RNAs (siRNAs) draws significant attention, but the gastrointestinal tract (GIT) has many biological barriers that limit the drugs' bioavailability. The aim of this work was to investigate the potential of micro- and nano-sized CaCO3 and PLA carriers for oral delivery of siRNA and reveal a relationship between the physicochemical features of these carriers and their biodistribution. RESEARCH DESIGN AND METHODS: In vitro stability of carriers was investigated in simulated gastric and intestinal fluids. Toxicity and cellular uptake were investigated on Caco-2 cells. The biodistribution profiles of the developed CaCO3 and PLA carriers were examined using different visualization methods, including SPECT, fluorescence imaging, radiometry, and histological analysis. The delivery efficiency of siRNA loaded carriers was investigated both in vitro and in vivo. RESULTS: Micro-sized carriers were accumulated in the stomach and later localized in the colon tissues. The nanoscale particles (100-250 nm) were distributed in the colon tissues. nPLA was also detected in small intestine. The developed carriers can prevent siRNA from premature degradation in GIT media. CONCLUSION: Our results reveal how the physicochemical properties of the particles, including their size and material type can affect their biodistribution profile and oral delivery of siRNA.

Dendrimer-mediated targeting of angiogenic biomarkers: therapeutic intervention against cancer.

INTRODUCTION: Development of novel vascular networks is a fundamental requirement for tumor growth and progression. In the last decade, biomarkers and underlying molecular pathways of angiogenesis have been intensely investigated to disrupt the initiation and progression of tumor angiogenesis. However, the clinical applications of anti-angiogenic agents are constrained due to toxic side effects, acquired drug resistance, and unavailability of validated biomarkers. AREA COVERED: This review discusses the development of dendrimeric nanocarriers that could be a promising domain to explore for the eradication of current challenges associated with angiogenesis-based cancer therapy. Novel drug-delivery approaches with subtle readouts and better understanding of molecular mechanisms have revealed that dendrimers comprise innate anti-angiogenic activity and incorporation of anti-angiogenic agents or gene-silencing RNA could lead to synergistic anti-angiogenic and anticancer effects with reduced side effects. EXPERT OPINION: Dendrimer-mediated targeting of angiogenic biomarkers has efficiently led to the vascular normalization, and rational linking of dendrimers with anti-angiogenic agent or siRNA or both might be a potential area to eradicate the current challenges of angiogenesis-based cancer therapy. However, drawbacks associated with the dendrimers-mediated targeting of angiogenic biomarkers, such as poor stability or small expression of these biomarkers on the normal cells, limit their application at market scale.