Lipid-polymer Hybrid Research Articles

Nanoparticle technology for mRNA: Delivery strategy, clinical application and developmental landscape.

The mRNA vaccine, a groundbreaking advancement in the field of immunology, has garnered international recognition by being awarded the prestigious Nobel Prize, which has emerged as a promising prophylactic and therapeutic modality for various diseases, especially in cancer, rare disease, and infectious disease such as COVID-19, wherein successful mRNA treatment can be achieved by improving the stability of mRNA and introducing a safe and effective delivery system. Nanotechnology-based delivery systems, such as lipid nanoparticles, lipoplexes, polyplexes, lipid-polymer hybrid nanoparticles and others, have attracted great interest and have been explored for mRNA delivery. Nanoscale platforms can protect mRNA from extracellular degradation while promoting endosome escape after endocytosis, hence improving the efficacy. This review provides an overview of diverse nanoplatforms utilized for mRNA delivery in preclinical and clinical stages, including formulation, preparation process, transfection efficiency, and administration route. Furthermore, the market situation and prospects of mRNA vaccines are discussed here.

Lipid-polymer hybrid nanoparticles loaded with N-acetylcysteine for the modulation of neuroinflammatory biomarkers in human iPSC-derived PSEN2 (N141I) astrocytes as a model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive impairment associated with the accumulation of beta-amyloid protein (Aβ). Aβ activates glial cells in the brain, increasing the secretion of proinflammatory cytokines, which leads to neuroinflammation and neuronal death. Currently, there are no effective treatments that cure or stop its progression; therefore, AD is considered a global health priority. The main limitations are the low drug bioavailability and impermeability of the blood-brain barrier (BBB). Fortunately, nanomedicine has emerged as a promising field for the development of new nanosystems for the controlled and targeted delivery of drugs to the brain. Therefore, in this work, lipid-polymer hybrid nanoparticles (LPHNPs) conjugated with transferrin (Tf) to facilitate crossing the BBB and loaded with N-acetylcysteine (NAC) for its anti-inflammatory effect were synthesized, and their physicochemical characterization was carried out. Subsequently, an in vitro model involving human astrocytes derived from induced pluripotent stem cells (iPSC) from an AD-diagnosed patient was developed, which was brought to a reactive state by stimulation with lipopolysaccharides (LPSs). The cell culture was treated with either Tf-conjugated LPHNPs loaded with NAC (NAC-Tf-LPHNPs) at 0.25 mg mL-1, or free NAC at 5 mM. The results showed that NAC-Tf-LPHNPs favorably modulated the expression of proinflammatory genes such as interleukin-1β (IL-1β), amyloid precursor protein (APP) and glial fibrillary acidic protein (GFAP). In addition, they reduced the secretion of the proinflammatory cytokines interleukin 6 (IL-6), IL-1β and interferon-gamma (INF-γ). Results for both cases were compared to the group of cells that did not receive any treatment. In contrast, free NAC only had this effect on the expression of IL-1β and the secretion of the cytokines IL-6 and INF-γ. These results indicate the potential of NAC-Tf-LPHNPs for AD treatment.

Antibacterial Activity of Epigallocatechin-3-gallate (EGCG) Loaded Lipid-chitosan Hybrid Nanoparticle against Planktonic Microorganisms.

Epigallocatechin-3-gallate (EGCG), a polyphenol derived from Green Tea, is one of the sources of natural bioactive compounds which are currently being developed as medicinal ingredients. Besides other biological activities, this natural compound exhibits anti-cariogenic effects. However, EGCG has low physical-chemical stability and poor bioavailability. Thus, the purpose of this study was to develop and characterize lipid-chitosan hybrid nanoparticle with EGCG and to evaluate its in vitro activity against cariogenic planktonic microorganisms. Lipid-chitosan hybrid nanoparticle (LCHNP-EGCG) were prepared by emulsion and sonication method in one step and characterized according to diameter, polydispersity index (PdI), zeta potential (ZP), encapsulation efficiency (EE), mucoadhesion capacity and morphology. Strains of Streptococcus mutans, Streptococcus sobrinus and Lactobacillus casei were treated with LCHNP- EGCG, and minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were evaluated. LCHNP-EGCG exhibited a size of 217.3 ± 5.1 nm with a low polydispersity index (0.17) and positive zeta potential indicating the presence of chitosan on the lipid nanoparticle surface (+33.7 mV). The LCHNP-EGCG showed a spherical morphology, high stability and a mucoadhesive property due to the presence of chitosan coating. In addition, the EGCG encapsulation efficiency was 96%. A reduction of almost 15-fold in the MIC and MBC against the strains was observed when EGCG was encapsulated in LCHNP, indicating the potential of EGCG encapsulation in lipid-polymer hybrid nanoparticles. Taking the results together, the LCHNP-EGCG could be an interesting system to use in dental care due to their nanometric size, mucoadhesive properties high antibacterial activity against relevant planktonic microorganisms.

Enhanced Cellular Immunity for Hepatitis B Virus Vaccine: A Novel Polyinosinic-Polycytidylic Acid-Incorporated Adjuvant Leveraging Cytoplasmic Retinoic Acid-Inducible Gene-Like Receptor Activation and Increased Antigen Uptake.

Conventional aluminum adjuvants exhibit limited cellular immunity. Polyinosinic-polycytidylic acid (poly I:C) activates cytoplasmic retinoic acid-inducible gene-like receptor (RLR), triggering strong T cell activation and cellular responses. However, when applied as an adjuvant, its limited endocytosis and restricted cytoplasmic delivery diminish its effectiveness and increase its toxicity. Hybrid polymer-lipid nanoparticle (PLNP) possesses numerous benefits such as good stability, reduced drug leakage, simple fabrication, easy property modulation, and excellent reproducibility compared to the lipid nanoparticle or the polymeric vector. Here, we developed a novel cationic polymer-lipid hybrid adjuvant capable of incorporating poly I:C to enhance cellular immunity. The hepatitis B surface antigen (HBsAg) was immobilized onto poly I:C-incorprated PLNP (PPLNP) via electrostatic interactions, forming the HBsAg/PPLNP vaccine formulation. The PPLNP adjuvant largely enhanced the cellular endocytosis and cytoplasmic transport of poly I:C, activating RLR followed by promoting type I interferon (IFN) secretion. Meanwhile, PPLNP obviously enhanced the antigen uptake, prolonged antigen retention at the site of administration, and facilitated enhanced transport of antigens to lymph nodes. The HBsAg/PPLNP nanovaccine led to amplified concentrations of antigen-specific immunoglobulin G (IgG), IFN-γ, granzyme B, and an enhanced IgG2a/IgG1 ratio, alongside the FasL+/CD8+ T cell activation, favoring a T helper 1 (TH1)-driven immune response. PPLNP, distinguished by its biocompatibility, ease of fabrication, and effectiveness in augmenting cellular immunity, holds significant promise as a new adjuvant.

Design, development, and evaluation of CDK-4/6 inhibitor loaded 4-carboxy phenyl boronic acid conjugated pH-sensitive chitosan lecithin nanoparticles in the management of breast cancer

Our main aim to design and develop a novel 4-carboxy phenyl boronic acid (4-CPBA) conjugated Palbociclib (PALB) loaded pH-sensitive chitosan lipid nanoparticles (PPCL) to enhance the anti-cancer efficacy of the PALB in in-vitro cell line studies by loading into 4-CPBA conjugated chitosan lipid nanoparticles. 4-CPBA was conjugated to chitosan by carbodiimide chemistry and formation of conjugate was confirmed by 1HNMR, ATR-FTIR spectroscopic techniques. Ionic-gelation method was used for the fabrication of PPCL and particles size, PDI, zeta potential were found to be 226.5 ± 4.3 nm, 0.271 ± 0.014 and 5.03 ± 0.42 mV. Presence of pH-sensitive biological macromolecule i.e. chitosan in the carrier system provides pH-sensitivity to PPCL and sustainedly released the drug upto 144 h. The PPCL exhibited approximately 7.2, 6.6, and 5-fold reduction in IC50 values than PALB in MCF-7, MDA-MB-231 and 4T1 cells. Receptor blocking assay concluded that the fabricated nanoparticles were internalized into MCF-7 cells might be through sialic acid-mediated endocytosis. PPCL caused extensive mitochondrial depolarization, enhanced ROS generation, apoptosis (DAPI nuclear staining, acridine orange/ ethidium bromide dual staining), and reduced % cell migration than pure PALB. It was concluded that the hybrid lipid-polymer nanoparticles provides an optimistic approach for the treatment of breast cancer.

EGFR-targeting peptide conjugated polymer-lipid hybrid nanoparticles for delivery of salinomycin to osteosarcoma.

Salinomycin (SAL) is a chemotherapeutic drug with anti-osteosarcoma efficacy, but its hydrophobic properties have hindered its application. Nanoparticles have been widely used as drug carriers to improve the solubility of hydrophobic drugs. The dodecapeptide GE11 has been shown to have great binding affinity to the epidermal growth factor receptor (EGFR), which is highly overexpressed in osteosarcoma. We designed novel SAL-loaded GE11-conjugated polymer-lipid hybrid nanoparticles (GE11-NPs-SAL) to target osteosarcoma. The characterization and antitumor activity of GE11-NPs-SAL were evaluated both in vitro and in vivo. The results showed that GE11-NPs-SAL had a size of ~100 nm with a high encapsulation efficacy of ~80%. Compared with the non-targeted nanoparticles, GE11-NPs-SAL showed increased internalization in osteosarcoma cells and improved therapeutic efficacy in osteosarcoma both in vitro and in vivo. GE11-NPs-SAL is a promising treatment for osteosarcoma.

Potentiating humoral and cellular immunity using a novel hybrid polymer-lipid nanoparticle adjuvant for HBsAg-VLP vaccine

Aluminium adjuvants are commonly used in vaccines to stimulate the immune system, but they have limited ability to promote cellular immunity which is necessary for clearing viral infections like hepatitis B. Current adjuvants that do promote cellular immunity often have undesired side effects due to the immunostimulants they contain. In this study, a hybrid polymer lipid nanoparticle (HPLNP) was developed as an efficient adjuvant for the hepatitis B surface antigen (HBsAg) virus-like particle (VLP) vaccine to potentiate both humoral and cellular immunity. The HPLNP is composed of FDA approved polyethylene glycol-b-poly (l-lactic acid) (PEG-PLLA) polymer and cationic lipid 1, 2-dioleoyl-3-trimethylammonium-propane (DOTAP), and can be easily prepared by a one-step method. The cationic optimised vaccine formulation HBsAg/HPLNP (w/w = 1/600) can maximise the cell uptake of the antigen due to the electrostatic adsorption between the vaccine nanoparticle and the cell membrane of antigen-presenting cells. The HPLNP prolonged the retention of the antigen at the injection site and enhanced the lymph node drainage of antigen, resulting in a higher concentration of serum anti-HBsAg IgG compared to the HBsAg group or the HBsAg/Al group after the boost immunisation in mice. The HPLNP also promoted a strong Th1-driven immune response, as demonstrated by the significantly improved IgG2a/IgG1 ratio, increased production of IFN-γ, and activation of CD4 + and CD8 + T cells in the spleen and lymph nodes. Importantly, the HPLNP demonstrated no systemic toxicity during immunisation. The advantages of the HPLNP, including good biocompatibility, easy preparation, low cost, and its ability to enhance both humoral and cellular immune responses, suggest its suitability as an efficient adjuvant for protein-based vaccines such as HBsAg-VLP. These findings highlight the promising potential of the HPLNP as an HBV vaccine adjuvant, offering an alternative to aluminium adjuvants currently used in vaccines.

CRISPR-Cas12a powered hybrid nanoparticle for extracellular vesicle aggregation and in-situ microRNA detection

Efficient extracellular vesicle (EV) enrichment and timely internal RNA detection for cancer diagnostics are highly desirable and remain a challenge. Here, we report a rapid EV aggregation induced in-situ microRNA detection technology based on cationic lipid-polymer hybrid nanoparticles encapsulating cascade system of catalytic hairpin assembly and CRISPR-Cas12a (CLHN-CCC), allowing for EV enrichment in three-dimensional space and in-situ detection of internal microRNAs in one step within 30 min. The enrichment efficiency (>90%) of CLHN-CCC is demonstrated in artificial EVs, cell-secreted EVs and serum EVs, which is 5-fold higher than that of traditional ultracentrifugation. The sensitive detection of artificial EVs and internal miR-1290 was achieved with the limit of detection of 10 particles/μL and 0.07 amol, respectively. After lyophilization, CLHN-CCC shows no obvious loss of performance within 6 months, making it much more robust and user friendly. This technique could sensitively (sensitivity = 92.9%) and selectively (selectivity = 85.7%) identify low amount miR-1290 in serum EVs, distinguishing early-stage pancreatic cancer patients from healthy subjects, showing high potential for clinical applications.

Formulation of chitosan based lipid polymer hybrid nanocarrier system for oral delivery of tamoxifen citrate: Toxicological and hemocompatibility evaluation

The objective of the current work was to develop chitosan based lipid nanocarriers for the oral controlled release of tamoxifen citrate (TC). The ionic gelation method was used to develop various formulations with altered ratios of polymer, lipid, and emulsifier. The developed lipid hybrid nanoparticles (LHNPs) were characterized for particle size, polydispersity index, zeta potential, entrapment efficiency, SEM, DSC, FTIR, PXRD, in vitro release studies, stability studies, kinetic modeling, toxicity studies, and hemocompatibility assay. Particle size and entrapment efficiency of the developed formulations varied between 138.2 ± 4.2 nm to 281.8 ± 63.1 nm and 70.94 ± 0.29 % to 82.23 ± 0.02 %, respectively. The polydispersity index and zeta potential ranged from 0.199 ± 0.03 to 0.555 ± 0.01 and 17.9 ± 0.62 to 32.3 ± 0.36, respectively. Nano-sized, spherical in shape surfaces of developed particles were depicted by SEM. While removal of TC melting endotherm revealed by DSC analysis, suggested good thermal stability of LHNPs. FTIR verified that the components of the formulation do not interact chemically. PXRD depicted that the developed formulation has been successfully amorphized. In vitro release study revealed drug release, an initial burst drug release followed by the controlled release up to 72 h. Kinetic modeling exposed that all developed formulations showed a non-Fickian diffusion profile and were best fitted into Higuchi's square root and Korsmeyer-Peppas models. Toxicity investigations on female albino rabbits provided evidence for the compatibility and non-toxicity of developed particles with biological systems. Hemocompatibility assay showed that the developed system is compatible with blood and nontoxic. These investigations demonstrate the potential of developed LHNPs as a vehicle, aimed at controlled oral delivery of TC for better therapeutic applications in breast cancer.

Formulation of lipid polymer hybrid nanoparticles of the phytochemical Fisetin and its in vivo assessment against severe acute pancreatitis

Fisetin (FST) is a naturally occurring flavonol that has recently emerged as a bioactive phytochemical with an impressive array of biological activities. To the author knowledge, boosting the activity of FST against severe acute pancreatitis (SAP) through a nanostructured delivery system (Nanophytomedicine) has not been achieved before. Thereupon, FST-loaded lipid polymer hybrid nanoparticles (FST-loaded LPHNPs) were prepared through conjoined ultrasonication and double emulsion (w/o/w) techniques. Comprehensive in vitro and in vivo evaluations were conducted. The optimized nanoparticle formula displayed a high entrapment efficiency % of 61.76 ± 1.254%, high loading capacity % of 32.18 ± 0.734, low particle size of 125.39 ± 0.924 nm, low particle size distribution of 0.357 ± 0.012, high zeta potential of + 30.16 ± 1.416 mV, and high mucoadhesive strength of 35.64 ± 0.548%. In addition, it exhibited a sustained in vitro release pattern of FST. In the in vivo study, oral pre-treatment of FST-loaded LPHNPs protected against l-arginine induced SAP and multiple organ injuries in rats compared to both FST alone and plain LPHNPs, as well as the untreated group, proven by both biochemical studies, that included both amylase and lipase activities, and histochemical studies of pancreas, liver, kidney and lungs. Therefore, the study could conclude the potential efficacy of the novel phytopharmaceutical delivery system of FST as a prophylactic regimen for SAP and consequently, associated multiple organ injuries.

Microfluidic Devices for Precision Nanoparticle Production

In recent years, the field of drug delivery has seen a significant shift towards the exploration and utilization of nanoparticles (NPs) as versatile carriers for therapeutic agents. With its ability to provide exact control over NPs’ characteristics, microfluidics has emerged as a potent platform for the efficient and controlled synthesis of NPs. Microfluidic devices designed for precise fluid manipulation at the micro-scale offer a unique platform for tailoring NP properties, enabling enhanced control over NP properties such as size, morphology, and size distribution while ensuring high batch-to-batch reproducibility. Microfluidics can be used to produce liposomes, solid lipid nanoparticles, polymer-based NPs, and lipid-polymer hybrid NPs, as well as a variety of inorganic NPs such as silica, metal, metal oxide, quantum dots, and carbon-based NPs, offering precise control over composition and surface properties. Its unique precision in tailoring NP properties holds great promise for advancing NP-based drug delivery systems in both clinical and industrial settings. Although challenges with large-scale production still remain, microfluidics offers a transformative approach to NP synthesis. In this review, starting from the historical development of microfluidic systems, the materials used to create the systems, microfabrication methods, and system components will be discussed in order to provide the reader with an overview of microfluidic systems. In the following, studies on the fabrication of nanoparticles such as lipid NPs, polymeric NPs, and inorganic NPs in microfluidic devices are included.

Transdermal Delivery of Lornoxicam Hybrid Nanogel: Design, Preparation, Characterization, and In-Vitro Diffusion Evaluation

Lornoxicam was practically water insoluble and a nonsteroidal anti-inflammatory therapeutic agent thus associated with gastrointestinal tract (GIT) side effects. Lipid polymer hybrid nanocarriers (LPHNs)-based transdermal nanogel of lornoxicam was formulated to increase solubility of lornoxicam and sustained lornoxicam release that lead to eliminate GIT related side effect, prolong therapeutic activity and improve patient compliance .The lornoxicam LPHNs formulations (LH1-LH6) were prepared by microwaves based method. The conventional gel of lornoxicam (G) was prepared by solvent diffusion method. The LH1-LH6 was entered to characterization processes that were later used as a base to prepare lornoxicam hybrid nanogel formulations (LN1-LN6). The LN1-LN6 was tested for various evaluations. It was found that all the LH1-LH6 were show nanosize globules, low polydispersity index and acceptable surface charge, entrapment efficiency and drug loading. LH3 was the most optimized LPHNs due had lower particle size and higher lornoxicam release.The evaluation processes indicate stable organoleptic properties, high homogeneity, and acceptable values of pH. The comparability profile of the lornoxicam release from the lornoxicam nanogel formulations (LN1-LN6) and conventional lornoxicam gel (G) was in the following descending order: LN3 > LN2> LN1 > LN6 > LN5 > LN4 > G. The characterization and evaluation processes highly support promise transdermal delivery system to decrease pain and inflammation in musculoskeletal diseases.

Effect of lipid-polymer hybrid nanoparticles on the biophysical function and lateral structure of pulmonary surfactant: Mechanistic in vitro studies

The interaction between inhaled drug-loaded nanoparticles and pulmonary surfactant (PS) is critical for the efficacy and safety of inhaled nanomedicines. Here, we investigated the effect of small interfering RNA (siRNA)-loaded lipid-polymer hybrid nanoparticles (LPNs), which are designed for treatment of lung inflammation, on the physiological function of PS. By using biophysical in vitro methods we show that siRNA-loaded LPNs affect the biophysical function and lateral structure of PS. We used the Langmuir monolayer technique to demonstrate that LPNs display intrinsic surface activity by forming interfacial films that collapse at 49 mN/m, and they competitively inhibit the adsorption and spreading of PS components at the air–liquid interface. However, LPNs are excluded from the interface into the aqueous subphase at surface pressures above 49 mN/m, and hence they overcome the PS monolayer film barrier. Epifluorescence microscopy data revealed that LPNs influence the lateral structure of PS by: (i) affecting the nucleation, shape, and growth of compression-driven segregated condensed PS domains, and (ii) facilitating intermixing of liquid-expanded and tilted-condensed domains. However, the total surface area occupied by a highly condensed phase, presumably enriched in the highly surface tension-reducing dipalmitoylphosphatidylcholine, remained constant upon exposure to LPNs. These results suggest that surface-active LPNs influence the lateral structure of PS during translocation from the interface into the subphase, but LPNs do apparently not affect the biophysical function of PS under physiologically relevant conditions.

Lipid carriers for mRNA delivery.

Messenger RNA (mRNA) is the template for protein biosynthesis and is emerging as an essential active molecule to combat various diseases, including viral infection and cancer. Especially, mRNA-based vaccines, as a new type of vaccine, have played a leading role in fighting against the current global pandemic of COVID-19. However, the inherent drawbacks, including large size, negative charge, and instability, hinder its use as a therapeutic agent. Lipid carriers are distinguishable and promising vehicles for mRNA delivery, owning the capacity to encapsulate and deliver negatively charged drugs to the targeted tissues and release cargoes at the desired time. Here, we first summarized the structure and properties of different lipid carriers, such as liposomes, liposome-like nanoparticles, solid lipid nanoparticles, lipid-polymer hybrid nanoparticles, nanoemulsions, exosomes and lipoprotein particles, and their applications in delivering mRNA. Then, the development of lipid-based formulations as vaccine delivery systems was discussed and highlighted. Recent advancements in the mRNA vaccine of COVID-19 were emphasized. Finally, we described our future vision and perspectives in this field.

Enrichment of nano delivery platforms for mRNA-based nanotherapeutics.

Lipid-based nanoparticles (LNP) have shown significant progress in delivering mRNA for therapeutics, particularly with the success of coronavirus disease 2019 (COVID-19) vaccines. However, there are still challenges, such as organ-specific targeting, sustained protein expression, immunogenicity, and storage that need to be addressed. Therefore, there is interest in developing additional nano drug delivery systems (DDS) to complement LNP technology. Some of these include polymer, lipid-polymer hybrid, organic/inorganic hybrid nanostructure, and inorganic nanoparticle. In our opinion, LNP technology may not be suitable for every disease scenario in categories such as infection disease, cancer, pulmonary disease, autoimmune disorders and genetic rare disease (among others). This is because different diseases may require distinct administration routes, doses, and treatment durations, as well as considerations for biological barriers that may lower the efficacy and/or exert safety concern. In this perspective, we will highlight the need and potential for enhancing the diversity of nano delivery platforms for mRNA-based nanotherapeutics.

Polymer–lipid hybrid nanoparticles as potential lipophilic anticancer drug carriers

Nanocarrier systems are widely used for drug delivery applications, but limitations such as the use of synthetic surfactants, leakage of toxic drugs, and a poor encapsulation capacity remain as challenges. We present a new hybrid nanocarrier system that utilizes natural materials to overcome these limitations and improve the safety and efficacy of drug delivery. The system comprises a biopolymeric shell and a lipid core, encapsulating the lipophilic anticancer drug paclitaxel. Bovine serum albumin and dextran, in various molecular weights, are covalently conjugated via Maillard reaction to form the shell which serves as a stabilizer to maintain nanoparticle integrity. The properties of the system, such as Maillard conjugate concentration, protein/polysaccharide molar ratio, and polysaccharide molecular weight, are optimized to enhance nanoparticle size and stability. The system shows high stability at different pH conditions, high drug loading capacity, and effective in vitro drug release through the trigger of enzymes and passive diffusion. Serine proteases are used to digest the protein portion of the nanoparticle shell to enhance the drug release. This nanocarrier system represents a significant advancement in the field of nanomedicine, offering a safe and effective alternative for the delivery of lipophilic drugs.Graphical abstract

Development and In Vitro Evaluation of Crizotinib-Loaded Lipid-Polymer Hybrid Nanoparticles Using Box-Behnken Design in Non-small Cell Lung Cancer.

The goal of the study was to produce, optimize, characterize, and compare crizotinib-loaded lipid-polymer hybrid nanoparticles (CL-LPHNPs), representing a novel contribution to the existing literature, and to determine their anticancer activity in non-small cell lung cancer cells (NSCLC). Box-Behnken design was used to investigate the effect of three independent variables: polymer amount (X1), soy phosphatidylcholine (X2), and DSPE-PEG (X3), on three responses: particle size (Y1), polydispersity index (Y2), and zeta potential (Y3). Different parameters were evaluated on the optimized LPHNP formulations such as encapsulation efficiency, drug release study, transmission electron microscopy (TEM) image analysis, and in vitro cell evaluations. The mean particle size of the optimized formulation is between 120 and 220 nm with a PDI<0.2 and a zeta potential of -10 to -15 mV. The encapsulation efficiency values of crizotinib-loaded PLGA-LPHNPs (CL-PLGA-LPHNPs) and crizotinib-loaded PCL-LPHNPs (CL-PCL-LPHNPs) were 79.25±0.07% and 70.93±1.81%, respectively. Drug release study of CL-PLGA-LPHNPs and CL-PCL-LPHNPs showed a controlled and sustained release pattern as a result of core-shell type. Additionally, after 48 h, CL-PLGA-LPHNPs and CL-PCL-LPHNPs significantly reduced the viability of NCI-H2228 cells compared to free crizotinib. Moreover, CL-PLGA-LPHNPs and CL-PCL-LPHNPs exhibited a significant decrease in RAS, RAF, MEK, and ERK gene/protein expression levels after 48-h incubation. In conclusion, this pioneering study introduces lipid-polymer hybrid nanoparticles containing crizotinib as a novel treatment approach, uniting the advantages of a polymeric core and a lipid shell. The successful formulation optimization using Box-Behnken design yielded nanoparticles with adjustable size, remarkable stability, high drug loading, and a customizable drug release profile. Extensive investigations of key parameters, including particle size, PDI, ZP, TEM analysis, drug release, EE%, and in vitro evaluations, validate the potential of these nanoparticles. Moreover, the examination of two different polymers, PLGA and PCL, highlights their distinct impacts on nanoparticle performance. This research opens up new prospects for advanced therapeutic interventions with lipid-polymer hybrid nanoparticles.

A shift in focus towards precision oncology, driven by revolutionary nanodiagnostics; revealing mysterious pathways in colorectal carcinogenesis.

Multiple molecular mechanisms contribute to the development of colorectal cancer (CRC), with chromosomal instability (CIN) playing a significant role. CRC is influenced by mutations in several important genes, including APC, TP53, KRAS, PIK3CA, BRAF, and SMYD4. The three molecular subtypes of this disease are CIN, MSI-H, and CIMP (CpG-island phenotype). p53 dysfunction and aberrant Wnt signalling are common characteristics of CRC carcinogenesis. Despite advances in conventional therapy, metastatic CRC remains difficult to treat due to toxicity and resistance. Theranostics for cancer could significantly benefit from nanotechnology, as it would enable more targeted, individualised care with fewer side effects. Utilising functionalized nanoparticles has enabled MRI-guided gene therapy, magnetic hyperthermia, chemotherapy, immunotherapy, and photothermal/photodynamic therapy, thereby radically modifying the way cancer is treated. Active targeting using ligands or peptides on nanoparticles improves the delivery of drugs to cancer cells. Nanostructures such as drug peptide conjugates, chitosan nanoparticles, gold nanoparticles, carbon nanotubes, mesoporous silica-based nanoparticles, silver nanoparticles, hybrid lipid-polymer nanoparticles, iron oxide nanoparticles, and quantum dots may enable targeted drug delivery and enhanced therapeutic efficacy against CRC. Nanomedicines are presently being evaluated in clinical trials for the treatment of colorectal cancer, with the promise of more effective and individualised therapies. This article examines current nanomedicine patents for CRC, including the work of Delta-Fly, Merrimack, and Pfenning, Meaning & Partner, among others. In terms of future nanomedicine research and development, ligand production, particle size, and clearance are crucial factors. Lastly, the numerous nanostructures utilized in nanomedicine for targeted drug administration and diagnostics indicate optimistic prospects for enhancing CRC treatment. The successes of nanomedicine research and development for existing colon cancer treatments are also highlighted in this review.

Lipid-Polymer Hybrid Nanosystems: A Rational Fusion for Advanced Therapeutic Delivery.

Lipid nanoparticles (LNPs) are spherical vesicles composed of ionizable lipids that are neutral at physiological pH. Despite their benefits, unmodified LNP drug delivery systems have substantial drawbacks, including a lack of targeted selectivity, a short blood circulation period, and in vivo instability. lipid-polymer hybrid nanoparticles (LPHNPs) are the next generation of nanoparticles, having the combined benefits of polymeric nanoparticles and liposomes. LPHNPs are being prepared from both natural and synthetic polymers with various techniques, including one- or two-step methods, emulsification solvent evaporation (ESE) method, and the nanoprecipitation method. Varieties of LPHNPs, including monolithic hybrid nanoparticles, core-shell nanoparticles, hollow core-shell nanoparticles, biomimetic lipid-polymer hybrid nanoparticles, and polymer-caged liposomes, have been investigated for various drug delivery applications. However, core-shell nanoparticles having a polymeric core surrounded by a highly biocompatible lipid shell are the most commonly explored LPHNPs for the treatment of various diseases. In this review, we will shed light on the composition, methods of preparation, classification, surface functionalization, release mechanism, advantages and disadvantages, patents, and clinical trials of LPHNPs, with an emphasis on core-shell-structured LPHNPs.

Lipid-Polymer Hybrid Nanoparticles with Both PD-L1 Knockdown and Mild Photothermal Effect for Tumor Photothermal Immunotherapy.

In developing countries, the incidence of colorectal cancer (CRC) is on the rise. The combination of programmed cell death ligand-1 (PD-L1) siRNA (siPD-L1) and mild photothermal therapy (PTT) is a promising strategy for CRC treatment. In this study, dopamine-modified polyethylenimine (PEI) was prepared to fabricate an IR780 and siPD-L1 codelivery lipid-polymer hybrid nanoparticle (lip@PSD-siP) for the photothermal immunotherapy of CRC. The modification of dopamine can significantly reduce the cytotoxicity of PEI. lip@PSD-siP can be effectively taken up by CT26 cells and successfully escaped from lysosomes after entering the cells for 4 h. After CT26 cells were transfected with lip@PSD-siP, the PD-L1 positive cell rate decreased by 82.4%, and its PD-L1 knockdown effect was significantly stronger than the positive control Lipo3000-siP. In vivo studies showed that lip@PSD-siP-mediated mild PTT and efficient PD-L1 knockdown exhibited primary and distal tumor inhibition, metastasis delay, and rechallenged tumor inhibition. The treatment with lip@PSD-siP significantly promoted the maturation of dendritic cells in lymph nodes. The amount of T cell infiltration in the tumor tissues increased significantly, and the frequency of CD8+ T cells and CD4+ T cells was significantly higher than that of other groups. The percentage of immunosuppressive regulatory cells (Tregs) in the tumor tissue on the treatment side decreased by 88% compared to the PBS group, and the proportion of CD8+CD69+ T cells in the distal tumor tissue was 2.8 times that of the PBS group. The memory T cells of mice in the long-term antitumor model were analyzed. The results showed that after treatment with lip@PSD-siP, the frequency of effector memory T cells (Tem cells) significantly increased, suggesting the formation of immune memory.