bims-novged 2023-01-01 papers

bims-novged

Biomed News

on Non-viral vectors for gene delivery

Issue of 2023–01–01
fourteen papers selected by
the Merkel lab, Ludwig-Maximilians University

Messenger RNA in lipid nanoparticles rescues HEK 293 cells from lipid-induced mitochondrial dysfunction as studied by real time pulse chase NMR, RTPC-NMR, spectroscopy.
A highly efficient needle-free-injection delivery system for mRNA-LNP vaccination against SARS-CoV-2.
Incorporation of glycyrrhizic acid and polyene phosphatidylcholine in lipid nanoparticles ameliorates acute liver injury via delivering p65 siRNA.
Multiplexed shRNA-miRs as a candidate for anti HIV-1 therapy: strategies, challenges, and future potential.
Combination of Quercetin or/and siRNA-loaded DDAB-mPEG-PCL hybrid nanoparticles reverse resistance to Regorafenib in colon cancer cells.
Controlled growth factor delivery via a degradable poly(lactic acid) hydrogel microcarrier synthesized using degassed micromolding lithography.
Apocynin-loaded PLGA nanomedicine tailored with galactosylated chitosan intrigue asialoglycoprotein receptor in hepatic carcinoma: Prospective targeted therapy.
Reduced Cytotoxicity by Repetitive mRNA Transfection in Differentiated Neurons.
Pulmonary Administration of the Liposome-Based Adjuvant CAF01: Effect of Surface Charge on Mucosal Adjuvant Function.
miRNA nanoencapsulation to regulate the programming of the blood-brain barrier permeability by hypoxia.
Intra-articular nanodrug delivery strategies for treating osteoarthritis.
RNA interference: Promising approach for breast cancer diagnosis and treatment.
Liposome-mediated small RNA delivery to convert the macrophage polarity: A novel therapeutic approach to treat inflammatory uterine disease.
Cascade Delivery to Golgi Apparatus and On-Site Formation of Subcellular Drug Reservoir for Cancer Metastasis Suppression.

Sci Rep. 2022 Dec 24. 12(1): 22293

Messenger RNA in lipid nanoparticles rescues HEK 293 cells from lipid-induced mitochondrial dysfunction as studied by real time pulse chase NMR, RTPC-NMR, spectroscopy.

Nicholas Sciolino, Sergey Reverdatto, Aaron Premo, Leonard Breindel, Jianchao Yu, Gregory Theophall, David S Burz, Anna Liu, Todd Sulchek, Ann Marie Schmidt, Ravichandran Ramasamy, Alexander Shekhtman.

Analytical tools to study cell physiology are critical for optimizing drug-host interactions. Real time pulse chase NMR spectroscopy, RTPC-NMR, was introduced to monitor the kinetics of metabolite production in HEK 293T cells treated with COVID-19 vaccine-like lipid nanoparticles, LNPs, with and without mRNA. Kinetic flux parameters were resolved for the incorporation of isotopic label into metabolites and clearance of labeled metabolites from the cells. Changes in the characteristic times for alanine production implicated mitochondrial dysfunction as a consequence of treating the cells with lipid nanoparticles, LNPs. Mitochondrial dysfunction was largely abated by inclusion of mRNA in the LNPs, the presence of which increased the size and uniformity of the LNPs. The methodology is applicable to all cultured cells.

DOI: https://doi.org/10.1038/s41598-022-26444-z
Nano Today. 2023 Feb;48 101730

A highly efficient needle-free-injection delivery system for mRNA-LNP vaccination against SARS-CoV-2.

Shanhong Mao, Shiyou Li, Yuxin Zhang, Luoxin Long, Junfeng Peng, Yuanyan Cao, Jessica Z Mao, Xin Qi, Qi Xin, Guoliang San, Jing Ding, Jun Jiang, Xuejiao Bai, Qianting Wang, Pengfei Xu, Huan Xia, Lijun Lu, Liangzhi Xie, Desheng Kong, Shuangli Zhu, Wenbo Xu.

  Despite the various vaccines that have been developed to combat the coronavirus disease 2019 (COVID-19) pandemic, the persistent and unpredictable mutations of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) require innovative and unremitting solutions to cope with the resultant immune evasion and establish a sustainable immune barrier. Here we introduce a vaccine-delivery system with a combination of a needle-free injection (NFI) device and a SARS-CoV-2-Spike-specific mRNA-Lipid Nanoparticle (LNP) vaccine. The benefits are duller pain and a significant increase of immunogenicity compared to the canonical needle injection (NI). From physicochemical and bioactivity analyses, the structure of the mRNA-LNP maintains stability upon NFI, contradictory to the belief that LNPs are inclined towards destruction under the high-pressure conditions of NFI. Moreover, mRNA-LNP vaccine delivered by NFI induces significantly more binding and neutralizing antibodies against SARS-CoV-2 variants than the same vaccine delivered by NI. Heterogeneous vaccination of BA.5-LNP vaccine with NFI enhanced the generation of neutralizing antibodies against Omicron BA.5 variants in rabbits previously vaccinated with non-BA.5-specific mRNA-LNP or other COVID-19 vaccines. NFI parameters can be adjusted to deliver mRNA-LNP subcutaneously or intramuscularly. Taken together, our results suggest that NFI-based mRNA-LNP vaccination is an effective substitute for the traditional NI-based mRNA-LNP vaccination.

Keywords:  Lipid Nanoparticle (LNP); Needle injection (NI); Needle-free injection (NFI); SARS-CoV-2; mRNA vaccine

DOI:  https://doi.org/10.1016/j.nantod.2022.101730
Nanomedicine. 2022 Dec 27. pii: S1549-9634(22)00135-6. [Epub ahead of print] 102649

Incorporation of glycyrrhizic acid and polyene phosphatidylcholine in lipid nanoparticles ameliorates acute liver injury via delivering p65 siRNA.

Qiming Yin, Xiang Song, Peng Yang, Wen Yang, Xinyu Li, Xuejun Wang, Shengqi Wang.

  Liver injury caused by hepatitis is the pathological basis of varied hepatic diseases with high morbidity and mortality. Although siRNA appears promising in therapeutics of hepatitis, efficient and safe delivery remains a challenge. In this study, we developed a new strategy of incorporating glycyrrhizic acid (GA) and polyene phosphatidylcholine (PPC) into lipid nanoparticles (GA/PPC-modified LNPs), which was capable of promoting cellular uptake, enhancing gene-silencing, reducing cytotoxicity and improving siRNA stability. GA/PPC-modified LNP and siRNA lipoplex targeting NF-κB, a key mediator of inflammation, mitigates acute liver injury, as assessed by liver histology, hematological and pro-inflammatory cytokine analysis. Furthermore, GA/PPC-modified LNPs reveal efficiently intracellular delivery of antisense oligonucleotides (ASOs) and mRNA inhibiting viral infection. In conclusion, GA/PPC-modified LNPs could be used as a promising delivery system for nucleic acid-based therapy.

Keywords:  Acute liver injury; Glycyrrhizic acid; Inflammation; Lipid nanoparticle

DOI:  https://doi.org/10.1016/j.nano.2022.102649
J Genet Eng Biotechnol. 2022 Dec 28. 20(1): 172

Multiplexed shRNA-miRs as a candidate for anti HIV-1 therapy: strategies, challenges, and future potential.

Jyotsna Jai, Deborah Shirleen, Christian Hanbali, Pamela Wijaya, Theresia Brigita Anginan, William Husada, Muhammad Yogi Pratama.

  The spread of HIV is on the rise and has become a global issue, especially for underdeveloped and developing countries. This is due to the fact that HIV majorly occurs asymptomatically and is implausible for early diagnosis. Recent advances in research and science have enabled the investigation of a new potential treatment involving gene-based therapy, known as RNA interference (RNAi) that will direct gene silencing and further compensate for natural variants and viral mutants. Several types of small regulatory RNA are discussed in this present study, including microRNA (miRNA), small interfering RNA (siRNA), and short hairpin RNA (shRNA).This paper examines the mechanism of RNAi as a viable HIV therapy, using a minimum of four shRNAs to target both dispensable host components (CCR5) and viral genes (Gag, Env, Tat, Pol I, Pol II and Vif). Moreover, a multiplexed mechanism of shRNAs and miRNA is known to be effective in preventing viral escape due to mutation as the miRNA develops a general polycistronic platform for the expression of a large amount of shRNA-miRs. Several administration methods as well as the advantages of this RNAi treatment are also discussed in this study. The administration methods include (1) ex vivo delivery with the help of viral vectors, nanoparticles, and electroporation, (2) nonspecific in vivo delivery using non-viral carriers including liposomes, dendrimers and aptamers, as well as (3) targeted delivery that uses antibodies, modified nanoparticles, nucleic acid aptamers, and tissue-specific serotypes of AAV. Moreover, the advantages of this treatment are related to the effectiveness in silencing the HIV gene, which is more compatible compared to other gene therapy treatments, such as ZFN, TALEN, and CRISPR/Cas9.

Keywords:  Gene silencing; Gene therapy; HIV-1 therapy; Multiplexed shRNA-miRs; RNA interference; miRNA; shRNA; siRNA

DOI:  https://doi.org/10.1186/s43141-022-00451-z
BMC Complement Med Ther. 2022 Dec 27. 22(1): 340

Combination of Quercetin or/and siRNA-loaded DDAB-mPEG-PCL hybrid nanoparticles reverse resistance to Regorafenib in colon cancer cells.

Shabnam Shahidi, Kobra Rostamizadeh, Mojtaba Fathi, Keivan Nedaei, Ali Ramazani.

   BACKGROUND: Colorectal cancer (CRC) is the second leading cause of cancer death. Although Regorafenib showed survival benefits in patients with CRC, reports imply the recurrence of malignant phenotype resulting from chemotherapy. Evidence demonstrated that a5β1 integrin plays an important role in the Regorafenib treatment, which, may be led to resistance. In this study, the effects of /siRNA or/ and Quercetin loaded DDAB-mPEG-PCLnanoparticles could reverse this resistance phenotype in colon cancer cells in vitro.
METHODS: Regorafenib-resistant Ls-180 colon cancer cell line was developed by long-term exposure to Regorafenib. Quercetin and Regorafenib were separately encapsulated into mPEG-PCL micelles through the nano-precipitation method and characterized by DLS. Optimized doses of Quercetin and Regorafenib were used for combination therapy of resistant cells followed cytotoxicity study using MTT. Gene expression levels of the β1 subunit of integrin were determined by the real-time method of RT-PCR.
RESULTS: Developed Regorafenib resistant LS-180 showed to have Regorafenib IC50 of 38.96 ± 1.72 µM whereas IC50 in non-resistant cells were 8.51 ± 0.29 µM, which meaningful was lower statistically compared to that of a resistant one. The β1 mRNA level of whole α5β1 integrin was significantly higher in the resistant cells compared to those of non-resistant ones. Gene expression levels in each siRNA-loaded nanoparticle and Quercetin-loaded one were lower than that in mock experiments. Finally, when these two types of nanoparticles were used to treat resistant cells, gene expression decrease of integrin indicated a greater effect that could be capable of reverse resistancy.
CONCLUSION: Results of this study demonstrated another confirmation of involving integrins in cancer resistance following chemotherapy using Regorafenib. Also, it indicated how using siRNA targeting integrin could enhance the plant derivatives like Quercetin effects to reverse resistance in vitro.

Keywords:  Colorectal cancer; DDAB mPEG-PCL; Quercetin; Regorafenib; α5β1integrin

DOI:  https://doi.org/10.1186/s12906-022-03787-8
Colloids Surf B Biointerfaces. 2022 Dec 15. pii: S0927-7765(22)00772-X. [Epub ahead of print]222 113088

Controlled growth factor delivery via a degradable poly(lactic acid) hydrogel microcarrier synthesized using degassed micromolding lithography.

Wookyoung Jang, Seok Joon Mun, Soung-Yon Kim, Ki Wan Bong.

  Controlled and targeted delivery of growth factors to biological environments is important for tissue regeneration. Polylactic acid (PLA) hydrogel microparticles are attractive carriers for the delivery of therapeutic cargoes based on their superior biocompatibility and biodegradability, uniform encapsulation of cargoes, and non-requirement of organic solvents during particle synthesis. In this study, we newly present controlled growth factor delivery utilizing PLA-based hydrogel microcarriers synthesized via degassed micromolding lithography (DML). Based on the direct gelation procedure from the single-phase aqueous precursor in DML, bovine serum albumin, a model protein of growth factor, and fibroblast growth factor were encapsulated into microparticles with uniform distribution. In addition, by tuning the monomer concentration and adding a hydrolytically stable crosslinker, the release of encapsulated cargoes was efficiently controlled and extended to 2 weeks. Finally, we demonstrated the biological activity of encapsulated FGF-2 in PLA-based microparticles using a fibroblast proliferation assay.

Keywords:  Biodegradation; Controlled release; Growth factor; Hydrogel; Microparticle

DOI:  https://doi.org/10.1016/j.colsurfb.2022.113088
Int J Pharm. 2022 Dec 23. pii: S0378-5173(22)01091-2. [Epub ahead of print]631 122536

Apocynin-loaded PLGA nanomedicine tailored with galactosylated chitosan intrigue asialoglycoprotein receptor in hepatic carcinoma: Prospective targeted therapy.

Hend Mohamed Anter, Reham Mokhtar Aman, Dina Ibrahim Ali Othman, Khaled M Elamin, Irhan Ibrahim Abu Hashim, Mahasen Mohamed Meshali.

  Nature serves as a priceless source for phytomedicines to treat different types of cancer, including hepatocellular carcinoma (HCC). Apocynin (APO), an anti-cancer phytomedicine, is a particular nicotinamide adenine dinucleotide phosphate-oxidase (NADPH-oxidase) inhibitor, which has recently dawned for its multilateral pharmacological activities. As far as we are aware, no investigation has been carried out yet to develop a targeted-nanostructured delivery system of APO to HCC. Consequently, chitosan derivative with galactose groups namely; galactosylated chitosan (GC), particularly recognized by the asialoglycoprotein receptor (ASGR), was synthesized and its chemical structure was thoroughly characterized by substantial techniques. Afterwards, GC-coated nanoplatform for hepatocyte attachment "APO-loaded galactosylated chitosan-coated poly(d,l-lactide-co-glycolide) nanoparticles (APO-loaded GC-coated PLGA NPs)" was developed. The prosperous APO-loaded GC-coated PLGA NPs would be comprehensively appraised through extensive investigations. Their solid state characterization using Fourier transform-infrared spectroscopy, powder X-ray diffraction, and differential scanning calorimetry proved APO's encapsulation in the polymeric matrix. Transmission electron microscopy imaging of the investigated NPs highlighted their spherical architecture with a nanosized range and a characteristic halo-like appearance traceable to the GC coating of the NPs' surface. Saliently, the results of in vitro cytotoxicity screening revealed the spectacular anti-cancer efficacy of APO-loaded GC-coated PLGA NPs formula against the HepG2 cell line. Moreover, the fluorescence microscope disclosed the distinguished cellular uptake of such formula via ASGPR mediated endocytosis. Inclusively, a multifunctional nano-phytomedicine delivery system with a promising active hepatocyte-targeting, effective uptake into HepG2 cells, and sustained drug release pattern was successfully developed.

Keywords:  Anti-cancer; Apocynin; Asialoglycoprotein receptor mediated endocytosis; Galactosylated chitosan; Hepatocellular carcinoma; Nano-phytomedicine

DOI:  https://doi.org/10.1016/j.ijpharm.2022.122536
Int J Stem Cells. 2022 Dec 31.

Reduced Cytotoxicity by Repetitive mRNA Transfection in Differentiated Neurons.

Seung Hwan Ko, Jin Sun Kang, Sang-Mi Kim, Eun-Hye Lee, Chang-Hwan Park.

   Background and Objectives: mRNA-based protein expression technology has been used to express functional proteins. We have previously generated dopamine neurons from rat-embryo derived neural precursor cells (NPCs) through repeated transfection of synthetic transcription factor mRNA encoding dopamine-inducible genes. However, NPCs began to die approximately 10 d post-transfection. In this study, we examined a long-term transfection protocol that did not affect cell viability.
Methods and Results: Experiments were performed in eight groups sorted according to the start date of mRNA transfection. mRNA was transfected into NPCs daily for 21 d and live cell images of each group were recorded. NPCs which were differentiated for more than five days showed sustained gene expression and appreciable viability despite daily mRNA transfection for 21 d.
Conclusions: Repeated mRNA transfection requires cells with a sufficient differentiation period.

Keywords:  Delayed initiation; Neuron survival; Neuronal differentiation; mRNA transfection

DOI:  https://doi.org/10.15283/ijsc22125
Mol Pharm. 2022 Dec 30.

Pulmonary Administration of the Liposome-Based Adjuvant CAF01: Effect of Surface Charge on Mucosal Adjuvant Function.

Olivia Amanda Oest Müllertz, Peter Andersen, Dennis Christensen, Camilla Foged, Aneesh Thakur.

  Mucosal surfaces of the lungs represent a major site of entry for airborne pathogens, and pulmonary administration of vaccines is an attractive strategy to induce protective mucosal immunity in the airways. Recently, we demonstrated the potential of pulmonary vaccination with the tuberculosis subunit antigen H56 adjuvanted with the cationic liposomal adjuvant formulation CAF01, which consists of the cationic lipid dimethyldioctadecylammonium (DDA) bromide and the synthetic cord factor trehalose-6,6'-dibehenate. However, the cationic charge of DDA represents a major safety challenge. Hence, replacing DDA with a safer zwitterionic or anionic phospholipid is an attractive approach to improve vaccine safety, but the effect of liposomal surface charge on the induction of mucosal immunity after airway immunization is poorly understood. Here, we investigated the effect of surface charge by replacing the cationic DDA component of CAF01 with zwitterionic dipalmitoylphosphatidylcholine (DPPC) or anionic dipalmitoylphosphatidylglycerol (DPPG), and we show that charge modification enhances antigen-specific pulmonary T-cell responses against co-formulated H56. We systematically replaced DDA with either DPPC or DPPG and found that these modifications resulted in colloidally stable liposomes that have similar size and morphology to unmodified CAF01. DPPC- or DPPG-modified CAF01 displayed surface charge-dependent protein adsorption and induced slightly higher follicular helper T cells and germinal center B cells in the lung-draining lymph nodes than unmodified CAF01. In addition, modified CAF01 induced significantly higher levels of H56-specific Th17 cells and polyfunctional CD4+ T cells in the lungs, as compared to unmodified CAF01. However, the strong H56-specific humoral responses induced by CAF01 in the lungs and spleen were not influenced by surface charge. Hence, these results provide insights into the importance of surface charge for liposomal adjuvant function and can also guide the design of safe pulmonary subunit vaccines against other mucosal pathogens.

Keywords:  H56/CAF01 vaccine; drug delivery; liposomes; mucosal adjuvant; pulmonary immunization; surfactant phospholipids

DOI:  https://doi.org/10.1021/acs.molpharmaceut.2c00634
Curr Res Pharmacol Drug Discov. 2022 ;3 100129

miRNA nanoencapsulation to regulate the programming of the blood-brain barrier permeability by hypoxia.

Esteban G Figueroa, Aitor Caballero-Román, Josep R Ticó, Montserrat Miñarro, Anna Nardi-Ricart, Alejandro González-Candia.

  Central nervous system (CNS)-related diseases are difficult to treat as most therapeutic agents they cannot reach the brain tissue, mainly due to the blood-brain barrier (BBB), arguably the tightest barrier between the human body and cerebral parenchyma, which routinely excludes most xenobiotic therapeutics compounds. The BBB is a multicellular complex that structurally forms the neurovascular unit (NVU) and is organized by neuro-endothelial and glial cells. BBB breakdown and dysfunction from the cerebrovascular cells lead to leakages of systemic components from the blood into the CNS, contributing to neurological deficits. Understanding the molecular mechanisms that regulate BBB permeability and disruption is essential for establishing future therapeutic strategies to restore permeability and improve cerebrovascular health. MicroRNAs (miRNAs), a type of small non-coding RNAs, are emerging as an important regulator of BBB integrity by modulating gene expression by targeting mRNA transcripts. miRNAs is implicated in the development and progression of various illnesses. Conversely, nanoparticle carriers offer unprecedented opportunities for cell-specific controlled delivery of miRNAs for therapeutic purposes. In this sense, we present in this graphical review critical evidence in the regulation of cell junction expression mediated by miRNAs induced by hypoxia and for the use of nanoparticles for the delivery of miRNA-based therapeutics in the treatment of BBB permeability.

Keywords:  Epigenetic; Hypoxia; Nanoparticle; Nose-to-brain; miRNA

DOI:  https://doi.org/10.1016/j.crphar.2022.100129
Drug Discov Today. 2022 Dec 27. pii: S1359-6446(22)00475-5. [Epub ahead of print] 103482

Intra-articular nanodrug delivery strategies for treating osteoarthritis.

Dongyang Zhou, Fengjin Zhou, Shihao Sheng, Yan Wei, Xiao Chen, Jiacan Su.

  Osteoarthritis (OA) is characterized by progressive cartilage degeneration. Pharmaceutical intervention remains a main treatment approach. However, drug delivery via intra-articular administration (IA) can be restricted by rapid clearance, the dense and highly negatively charged extracellular matrix (ECM) of cartilage, and uneven distribution of diseased chondrocytes. Nanodrug delivery systems, such as liposomes, micelles, and nanoparticles (NPs), have shown great potential to prolong intra-articular residence, penetrate the ECM, and achieve diseased chondrocyte-specific delivery. In this review, we discuss the challenges associated with intra-articular drug delivery in OA and the nanodrug delivery strategies developed to overcome these challenges. It is anticipated that these nanodrug delivery strategies will advance IA of drugs into broader applications in OA treatment.

Keywords:  intra-articular administration; nanodrug delivery strategies; osteoarthritis

DOI:  https://doi.org/10.1016/j.drudis.2022.103482
Cell Biol Int. 2022 Dec 26.

RNA interference: Promising approach for breast cancer diagnosis and treatment.

Elham Allahyari, Kobra Velaei, Zohreh Sanaat, Nazila Jalilzadeh, Amir Mehdizadeh, Mohammad Rahmati.

  Today, cancer is one of the main health-related challenges, and in the meantime, breast cancer (BC) is one of the most common cancers among women, with an alarming number of incidences and deaths every year. For this reason, the discovery of novel and more effective approaches for the diagnosis, treatment, and monitoring of the disease are very important. In this regard, scientists are looking for diagnostic molecules to achieve the above-mentioned goals with higher accuracy and specificity. RNA interference (RNAi) is a posttranslational regulatory process mediated by microRNA intervention and small interfering RNAs. After transcription and edition, these two noncoding RNAs are integrated and activated with the RNA-induced silencing complex (RISC) and AGO2 to connect the target mRNA by their complementary sequence and suppress their translation, thus reducing the expression of their target genes. These two RNAi categories show different patterns in different BC types and stages compared to healthy cells, and hence, these molecules have high diagnostic, monitoring, and therapeutic potentials. This article aims to review the RNAi pathway and diagnostic and therapeutic potentials with a special focus on BC.

Keywords:  RNAi; breast cancer; miRNA; siRNA

DOI:  https://doi.org/10.1002/cbin.11979
Mol Ther Nucleic Acids. 2022 Dec 13. 30 663-676

Liposome-mediated small RNA delivery to convert the macrophage polarity: A novel therapeutic approach to treat inflammatory uterine disease.

Mira Park, Hyeon-Ji Oh, Jieun Han, Seok-Ho Hong, Wooram Park, Haengseok Song.

  Macrophages are present in all tissues for maintaining tissue homeostasis, and macrophage polarization plays a vital role in alleviating inflammation. Therefore, specific delivery of polarization modulators to macrophages in situ is critical for treating inflammatory diseases. We demonstrate that a size-controlled miRNA-encapsulated macrophage-targeting liposomes (miR/MT-Lip) specifically targets macrophages to promote M1-to-M2 polarization conversion, alleviating inflammation without cytotoxicity. miR/MT-Lip, approximately 1.2 μm, showed excellent internalization through phagocytosis and/or macropinocytosis in macrophages. miR-10a/MT-Lip, but not scramble miR-Fluorescein amidite (FAM)/MT-Lip as control, effectively converted the polarization of lipopolysaccharide (LPS)-induced M1 macrophages to M2 in vitro. When miR-10a/MT-Lip was intravenously delivered to mice insulted with LPS for inflammation, the proportion of M2 macrophages was significantly increased without disturbing the population of other immune cells. Furthermore, scramble miR-FAM/MT-Lip was mainly detected in macrophages, but not other immune cells. When our miR/MT-Lip was administered to mice with Asherman's syndrome that suffer from infertility because of sterile uterine inflammation, macrophage-specific targeting of miR-10a/MT-Lip facilitated M1-to-M2 conversion for angiogenesis in the impaired uterus, resulting in restoration of healthy uterine conditions. The results indicate that our MT-Lip encapsulating small RNAs has excellent potential to treat various inflammatory disorders by fine-tuning macrophage polarization in vivo without any side effects.

Keywords:  Asherman’s syndrome; MT: Oligonucleotides: Therapies and Applications; inflammation; macrophage polarity; macrophage-targeting liposome; microRNA

DOI:  https://doi.org/10.1016/j.omtn.2022.11.018
Small. 2022 Dec 30. e2204747

Cascade Delivery to Golgi Apparatus and On-Site Formation of Subcellular Drug Reservoir for Cancer Metastasis Suppression.

Liqiang Chen, Peihang Jiang, Xinran Shen, Jiayan Lyu, Chendong Liu, Lian Li, Yuan Huang.

  As the foremost cause of cancer-related death, metastasis consists of three steps: invasion, circulation, and colonization. Only targeting one single phase of the metastasis cascade may be insufficient since there are many alternative routes for tumor cells to disseminate. Here, to target the whole cascade of metastasis, hybrid erythrocyte and tumor cell membrane-coated nanoparticle (Hyb-NP) is designed with dual functions of increasing circulation time and recognizing primary, circulating, and colonized tumors. After loading with monensin, a recently reported metastasis inhibitor, the delivery system profoundly reduces spontaneous metastasis in an orthotopic breast cancer model. Underlying mechanism studies reveal that Hyb-NP can deliver monensin to its action site in the Golgi apparatus, and in return, monensin can block the exocytosis of Hyb-NP from the Golgi apparatus, forming a reservoir-like subcellular structure. Notably, the Golgi apparatus reservoir displays three vital functions for suppressing metastasis initialization, including enhanced subcellular drug retention, metastasis-related cytokine release inhibition, and directional migration inhibition. Collectively, based on metastasis cascade targeting at the tissue level, further formation of the Golgi apparatus drug reservoir at the subcellular level provides a potential therapeutic strategy for cancer metastasis suppression.

Keywords:  Golgi apparatus targeting; drug reservoir; exocytosis blockade; metastasis suppression; monensin

DOI:  https://doi.org/10.1002/smll.202204747