Design of a versatile nanoparticle-based delivery system for intracellular and in vivo-targeted protein replacement therapy

<!DOCTYPE html> <html lang="it"> <head> <meta charset="utf-8"> <meta http-equiv="X-UA-Compatible" content="IE=edge"> <meta name="viewport" content="width=device-width, initial-scale=1.0"> <link rel="shortcut icon" href="/sr/favicon.ico" /> <link href="/sr/jstree/themes/default/style.min.css" rel="stylesheet" type="text/css"><link rel="stylesheet" href="/sr/jquery-ui/jquery-ui.min.css"> <link rel="stylesheet" type="text/css" href="https://static.cineca.it/jd/npm/jgrowl@1.4.9/jquery.jgrowl.min.css" /> <link rel="stylesheet" href="https://static.cineca.it/jd/npm/select2@4.0.13/dist/css/select2.min.css" /> <link rel="stylesheet" href="https://static.cineca.it/jd/npm/select2-bootstrap-5-theme@1.1.1/dist/select2-bootstrap-5-theme.min.css" /> <link rel="stylesheet" href="/sr/cineca/css/bootstrap-ricerca.min.css"> <link rel="stylesheet" href="/sr/local.css"><title>Design of a versatile nanoparticle-based delivery system for intracellular and in vivo-targeted protein replacement therapy</title> <script src="https://static.cineca.it/jd/npm/jquery@3.7.1/dist/jquery.min.js" integrity="sha512-v2CJ7UaYy4JwqLDIrZUI/4hqeoQieOmAZNXBeQyjo21dadnwR+8ZaIJVT8EE2iyI61OV8e6M8PP2/4hpQINQ/g==" crossorigin="anonymous"></script> <script type="text/javascript" src="/sr/jquery-ui/jquery-ui.min.js"></script> <script type="text/javascript" src="/sr/jquery-ui-i18n/jquery.ui.datepicker-it.latest.js" charset="utf-8"></script> <script src="https://static.cineca.it/jd/npm/bootstrap@5.2.3/dist/js/bootstrap.bundle.min.js" integrity="sha384-kenU1KFdBIe4zVF0s0G1M5b4hcpxyD9F7jL+jjXkk+Q2h455rYXK/7HAuoJl+0I4" crossorigin="anonymous"></script> <script src="https://static.cineca.it/jd/npm/jgrowl@1.4.9/jquery.jgrowl.min.js"></script> <script src="https://static.cineca.it/jd/npm/select2@4.0.13/dist/js/select2.full.min.js"></script> <script src="https://static.cineca.it/jd/npm/blueimp-tmpl@3.20.0/js/tmpl.min.js"></script><script type="text/javascript" src="/sr/jstree/jstree.min.js"></script><script type="text/javascript" src="/sr/jquery/js/jquery.displaytag-ajax-1.2.js"></script> <script src="https://static.cineca.it/jd/npm/js-cookie@3.0.5/dist/js.cookie.min.js" integrity="sha256-WCzAhd2P6gRJF9Hv3oOOd+hFJi/QJbv+Azn4CGB8gfY=" crossorigin="anonymous" referrerpolicy="no-referrer"></script> <script> var JQ = $; var j = $; </script> <script type="text/javascript"> </script> <script type="text/javascript" src="/sr/cineca/js/cilea.js?fwkVersion=25.2.1.2"></script> <script type="text/javascript" src="/sr/cineca/js/fragment.js?fwkVersion=25.2.1.2"></script> <script type="text/javascript" src="/sr/cineca/js/treeview.js?fwkVersion=25.2.1.2"></script> <script type="text/javascript" src="/sr/cineca/js/ap-tool.js?fwkVersion=25.2.1.2"></script> <span style="display:none;" id="rememberToSaveText">Attenzione: i dati modificati non sono ancora stati salvati. 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Advisor: Dr. Giovanni Signore (Istituto Italiano di Tecnologia [IIT]) and prof. Gian Michele Ratto (Scuola Normale Superiore)" xml:lang="en" /> <meta name="DCTERMS.available" content="2020-08-06T16:09:46Z" scheme="DCTERMS.W3CDTF" /> <meta name="DC.publisher" content="Scuola Normale Superiore" /> <meta name="DC.title" content="Design of a versatile nanoparticle-based delivery system for intracellular and in vivo-targeted protein replacement therapy" xml:lang="en" /> <meta name="DC.type" content="9 Tesi PhD::9.1 Tesi PhD" xml:lang="it" /> <meta name="DC.type" content="Doctoral Thesis" /> <meta name="DC.description" content="open" xml:lang="en" /> <meta name="DC.type" content="info:eu-repo/semantics/doctoralThesis" /> <meta name="DC.description" content="Protein replacement therapy is to-date one of the main clinical approaches
to treat a wide number of diseases that are correlated to a protein dysfunction
or absence. However, the systemic administration of proteins
rarely translates into a successful therapy, due to the fragile nature of these
molecules and their inability to reach specific targets in vivo. Pharmaceutical
technology strategies such as the encapsulation into a nanovector could
overcome the limits of protein administration, since nanovectors can protect
the payload from degradation and rapid clearance, and they can be
functionalized to reach specific targets. In this thesis, a nanoparticle (NP)
protein delivery system based on the biodegradable polymer poly(lactideco-
glycolide) (PLGA) was designed and tailored to the delivery of active
therapeutic proteins towards specific intracellular targets (i.e. the lysosome
and the cytosol) and in vivo districts, with a special attention to overcome
the blood brain barrier and deliver the therapeutics to the central nervous
system. The synthesis approach is based on the modification of proteins
into cross-linked enzyme aggregates (CLEAs) and their encapsulation into
PLGA with a straightforward and simple nanoprecipitation method. This
formulation strategy allowed excellent encapsulation efficiencies and catalytic
activity retention, taking significant steps forward compared to encapsulation
methods described so far in literature for PLGA NPs. The obtained
CLEA NP system was first applied to the delivery of lysosomal enzymes
involved in the treatment of lysosomal storage disorders, namely,
Infantile Neuronal Ceroid Lipofuscinosis and Krabbe Disease, and their
efficacy as enzyme replacement therapy agents was demonstrated both in vitro and in vivo. Indeed, brain-targeted versions of CLEA NPs were
demonstrated to promote the complete enzymatic activity recovery in cell
models of both diseases and to deliver the therapeutic payload to the cell
lysosome, that represents the intracellular target of LSDs. Moreover, upon
systemic administration CLEA NPs are able to cross the blood brain barrier
and restore the missing enzymatic activity in the brains of mouse models
of LSDs. Finally, the application of CLEA NPs was extended to allow delivery
even of cytosolic proteins, thus significantly expanding the therapeutic
applicability of this platform, by incorporation of an endosomal escape
agent in the formulation. Such modified CLEA NPs were demonstrated to
evade the endo-lysosomal route upon cell uptake and deliver therapeutic
enzymes also to the cytosol thanks to two distinct mechanisms, namely,
direct translocation through the cell membrane and endocytosis followed
by endosomal disrupture. The new formulation successfully allows the
delivery of a therapeutic enzyme to the cytosol and subsequent enzymatic
activity increase in vitro, adding strength to the versatility of this system as
protein delivery platform for virtually any protein-related disorder." xml:lang="en" /> <meta name="DC.description" content="open" xml:lang="en" /> <meta name="DCTERMS.bibliographicCitation" content="Design of a versatile nanoparticle-based delivery system for intracellular and in vivo-targeted protein replacement therapy / Galliani, Marianna; relatore: Ratto, Gian Michele; Scuola Normale Superiore, 12-Nov-2019." xml:lang="en" /> <meta name="DC.description" content="Fisica" xml:lang="it" /> <meta name="DC.subject" content="Biophysics" xml:lang="en" /> <meta name="DC.subject" content="nanoparticle (NP) protein delivery system" xml:lang="en" /> <meta name="DC.subject" content="nanovector" xml:lang="en" /> <meta name="DC.subject" content="Physics" xml:lang="en" /> <meta name="DC.subject" content="polymer poly(lactideco- glycolide) (PLGA)" xml:lang="en" /> <meta name="DC.contributor" content="Classe di Scienze" xml:lang="*" /> <meta name="DC.contributor" content="22714" xml:lang="*" /> <meta name="DC.subject" content="Biophysics" xml:lang="*" /> <meta name="DC.subject" content="nanoparticle (NP) protein delivery system" xml:lang="*" /> <meta name="DC.subject" content="nanovector" xml:lang="*" /> <meta name="DC.subject" content="Physics" xml:lang="*" /> <meta name="DC.subject" content="polymer poly(lactideco- glycolide) (PLGA)" xml:lang="*" /> <meta name="DC.date" content="2023/10/04 01:57:52" xml:lang="*" scheme="DCTERMS.W3CDTF" /> <meta name="DC.date" content="1696377472334" xml:lang="*" scheme="DCTERMS.W3CDTF" /> <meta name="DC.description" content="Galliani, Marianna" /> <meta name="citation_title" content="Design of a versatile nanoparticle-based delivery system for intracellular and in vivo-targeted protein replacement therapy" /> <meta name="citation_author" content="Galliani, Marianna" /> <meta name="citation_author_email" content="marianna.galliani@sns.it" /> <meta name="citation_author_orcid" content="0000-0003-4147-7457" /> <meta name="citation_date" content="2019-11-12" /> <meta name="citation_abstract_html_url" content="https://ricerca.sns.it/handle/11384/85931" /> <meta name="citation_pdf_url" content="https://ricerca.sns.it/bitstream/11384/85931/1/MGalliani_Thesis_Final.pdf" /> <meta name="citation_language" content="en" /> <meta name="citation_keywords" content="FIS/07 FISICA APPLICATA (A BENI CULTURALI, AMBIENTALI, BIOLOGIA E MEDICINA)" /> <meta name="citation_publisher" content="Scuola Normale Superiore" /> <script type="text/javascript"> $(document).on('click', '.c-bn', function() { location.reload(); 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However, the systemic administration of proteins rarely translates into a successful therapy, due to the fragile nature of these molecules and their inability to reach specific targets in vivo. Pharmaceutical technology strategies such as the encapsulation into a nanovector could overcome the limits of protein administration, since nanovectors can protect the payload from degradation and rapid clearance, and they can be functionalized to reach specific targets. In this thesis, a nanoparticle (NP) protein delivery system based on the biodegradable polymer poly(lactideco- glycolide) (PLGA) was designed and tailored to the delivery of active therapeutic proteins towards specific intracellular targets (i.e. the lysosome and the cytosol) and in vivo districts, with a special attention to overcome the blood brain barrier and deliver the therapeutics to the central nervous system. The synthesis approach is based on the modification of proteins into cross-linked enzyme aggregates (CLEAs) and their encapsulation into PLGA with a straightforward and simple nanoprecipitation method. This formulation strategy allowed excellent encapsulation efficiencies and catalytic activity retention, taking significant steps forward compared to encapsulation methods described so far in literature for PLGA NPs. The obtained CLEA NP system was first applied to the delivery of lysosomal enzymes involved in the treatment of lysosomal storage disorders, namely, Infantile Neuronal Ceroid Lipofuscinosis and Krabbe Disease, and their efficacy as enzyme replacement therapy agents was demonstrated both in vitro and in vivo. Indeed, brain-targeted versions of CLEA NPs were demonstrated to promote the complete enzymatic activity recovery in cell models of both diseases and to deliver the therapeutic payload to the cell lysosome, that represents the intracellular target of LSDs. Moreover, upon systemic administration CLEA NPs are able to cross the blood brain barrier and restore the missing enzymatic activity in the brains of mouse models of LSDs. Finally, the application of CLEA NPs was extended to allow delivery even of cytosolic proteins, thus significantly expanding the therapeutic applicability of this platform, by incorporation of an endosomal escape agent in the formulation. Such modified CLEA NPs were demonstrated to evade the endo-lysosomal route upon cell uptake and deliver therapeutic enzymes also to the cytosol thanks to two distinct mechanisms, namely, direct translocation through the cell membrane and endocytosis followed by endosomal disrupture. The new formulation successfully allows the delivery of a therapeutic enzyme to the cytosol and subsequent enzymatic activity increase in vitro, adding strength to the versatility of this system as protein delivery platform for virtually any protein-related disorder.</p> <p class="searchIndexItemDescription citation">Design of a versatile nanoparticle-based delivery system for intracellular and in vivo-targeted protein replacement therapy / Galliani, Marianna; relatore: Ratto, Gian Michele; Scuola Normale Superiore, 12-Nov-2019.</p> <div class="row"> <div class="col-lg-12 col-xl-9"> <div class="card"> <div class="card-body"> <div> <h3 class="mb-1 text-secondary">Design of a versatile nanoparticle-based delivery system for intracellular and in vivo-targeted protein replacement therapy</h3> <h5> <em><span class="contributor internalContributor internalContributore3aace00-b9f4-4c98-e053-3705fe0acb7e m-1"><a href="/cris/rp/rp07567" class="authority author">Galliani, Marianna</a></span></em> </h5> <h5>2019</h5> <hr/> <h4 class="mb-1">Abstract</h4> Protein replacement therapy is to-date one of the main clinical approaches to treat a wide number of diseases that are correlated to a protein dysfunction or absence. However, the systemic administration of proteins rarely translates into a successful therapy, due to the fragile nature of these molecules and their inability to reach specific targets in vivo. Pharmaceutical technology strategies such as the encapsulation into a nanovector could overcome the limits of protein administration, since nanovectors can protect the payload from degradation and rapid clearance, and they can be functionalized to reach specific targets. In this thesis, a nanoparticle (NP) protein delivery system based on the biodegradable polymer poly(lactideco- glycolide) (PLGA) was designed and tailored to the delivery of active therapeutic proteins towards specific intracellular targets (i.e. the lysosome and the cytosol) and in vivo districts, with a special attention to overcome the blood brain barrier and deliver the therapeutics to the central nervous system. The synthesis approach is based on the modification of proteins into cross-linked enzyme aggregates (CLEAs) and their encapsulation into PLGA with a straightforward and simple nanoprecipitation method. This formulation strategy allowed excellent encapsulation efficiencies and catalytic activity retention, taking significant steps forward compared to encapsulation methods described so far in literature for PLGA NPs. The obtained CLEA NP system was first applied to the delivery of lysosomal enzymes involved in the treatment of lysosomal storage disorders, namely, Infantile Neuronal Ceroid Lipofuscinosis and Krabbe Disease, and their efficacy as enzyme replacement therapy agents was demonstrated both in vitro and in vivo. Indeed, brain-targeted versions of CLEA NPs were demonstrated to promote the complete enzymatic activity recovery in cell models of both diseases and to deliver the therapeutic payload to the cell lysosome, that represents the intracellular target of LSDs. Moreover, upon systemic administration CLEA NPs are able to cross the blood brain barrier and restore the missing enzymatic activity in the brains of mouse models of LSDs. Finally, the application of CLEA NPs was extended to allow delivery even of cytosolic proteins, thus significantly expanding the therapeutic applicability of this platform, by incorporation of an endosomal escape agent in the formulation. Such modified CLEA NPs were demonstrated to evade the endo-lysosomal route upon cell uptake and deliver therapeutic enzymes also to the cytosol thanks to two distinct mechanisms, namely, direct translocation through the cell membrane and endocytosis followed by endosomal disrupture. The new formulation successfully allows the delivery of a therapeutic enzyme to the cytosol and subsequent enzymatic activity increase in vitro, adding strength to the versatility of this system as protein delivery platform for virtually any protein-related disorder. </div> <div class="dspace-display-item tabbable page-tabs mt-3"> <h5> <ul class="nav nav-tabs border-bottom fw-bold"> <li class="nav-item"><a class="nav-link active" href="#tab_default" onclick="changeItemView('simple');" data-bs-toggle="tab">Scheda breve</a></li> <li class="nav-item"><a class="nav-link " href="#tab_default" onclick="changeItemView('complete');" data-bs-toggle="tab">Scheda completa</a></li> <li class="nav-item"><a class="nav-link " href="#tab_default" onclick="changeItemView('full');" data-bs-toggle="tab">Scheda completa (DC)</a></li> <li class="nav-item"><a class="nav-link" onclick="location.href='/cris/item/11384/85931/statistics'" data-bs-toggle="tab"><span class="far fa-chart-bar"></span></a></li> </ul> </h5> <div class="tab-content"> <div class="tab-pane active fade show" id="tab_default"> <div class="itemDisplayTable container-fluid g-3"> <div class="line form-group row metadataFieldValue pt-2 pb-2 dc_date_issued" id="dc.date.issued_line" > <div class="line-label col-md-12"><label for="dc.date.issued" class="control-label metadataFieldLabel dc_date_issued"> <span class="line-label-text">Data di discussione</span> </label></div> <div class="line-content col-sm-12" id="dc.date.issued_content"> <em>12-nov-2019</em> </div> </div> <div class="line form-group row metadataFieldValue pt-2 pb-2 dc_authority_academicField2000" id="dc.authority.academicField2000_line" > <div class="line-label col-md-12"><label for="dc.authority.academicField2000" class="control-label metadataFieldLabel dc_authority_academicField2000"> <span class="line-label-text">Settore Scientifico Disciplinare della tesi (validi fino a 24/06/2024)</span> </label></div> <div class="line-content col-sm-12" id="dc.authority.academicField2000_content"> <em>FIS/07 FISICA APPLICATA (A BENI CULTURALI, AMBIENTALI, BIOLOGIA E MEDICINA)</em> </div> </div> <div class="line form-group row metadataFieldValue pt-2 pb-2 dc_description_phdCourse" id="dc.description.phdCourse_line" > <div class="line-label col-md-12"><label for="dc.description.phdCourse" class="control-label metadataFieldLabel dc_description_phdCourse"> <span class="line-label-text">Corso PhD</span> </label></div> <div class="line-content col-sm-12" id="dc.description.phdCourse_content"> <em>Fisica</em> </div> </div> <div class="line form-group row metadataFieldValue pt-2 pb-2 dc_subject_keywordseng" id="dc.subject.keywordseng_line" > <div class="line-label col-md-12"><label for="dc.subject.keywordseng" class="control-label metadataFieldLabel dc_subject_keywordseng"> <span class="line-label-text">Parole chiave</span> </label></div> <div class="line-content col-sm-12" id="dc.subject.keywordseng_content"> <em>Biophysics<br/>nanoparticle (NP) protein delivery system<br/>nanovector<br/>Physics<br/>polymer poly(lactideco- glycolide) (PLGA)</em> </div> </div> <div class="line form-group row metadataFieldValue pt-2 pb-2 dc_publisher_name" id="dc.publisher.name_line" > <div class="line-label col-md-12"><label for="dc.publisher.name" class="control-label metadataFieldLabel dc_publisher_name"> <span class="line-label-text">Editore</span> </label></div> <div class="line-content col-sm-12" id="dc.publisher.name_content"> <em>Scuola Normale Superiore</em> </div> </div> <div class="line form-group row metadataFieldValue pt-2 pb-2 dc_authority_advisor" id="dc.authority.advisor_line" > <div class="line-label col-md-12"><label for="dc.authority.advisor" class="control-label metadataFieldLabel dc_authority_advisor"> <span class="line-label-text">Relatore/i interno/i</span> </label></div> <div class="line-content col-sm-12" id="dc.authority.advisor_content"> <em>Ratto, Gian Michele<br/>Signore, Giovanni</em> </div> </div> <div class="line form-group row metadataFieldValue pt-2 pb-2 dspace_collection" id="dspace_collection_line" > <div class="line-label col-md-12"><label for="dspace_collection" class="control-label metadataFieldLabel dspace_collection"> <span class="line-label-text">Appare nelle tipologie:</span> </label></div> <div class="line-content col-sm-12" id="dspace_collection_content"> <a href="/handle/11384/78634">9.1 Tesi PhD</a> </div> </div> </div> </div> </div> </div></div> </div> <script type="text/x-tmpl" id="tmpLicenseDetail"> <div class="d-flex align-items-center"> {% if (o.licenseImage != null) { %} <div class="flex-shrink-0"> <img src="{%= o.licenseImage %}" /> </div> {% } %} <div class="flex-grow-1 ms-3"> {%# o.licenseName %} </div> </div> </script> <div id="bitstreams" class="card bg-white mt-2"> <div class="card-header">File in questo prodotto:</div> <table class="table card-body"> <tr> <th id="t1" class="standard">File</th> <th id="t3" class="standard d-none 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<div class="col-lg-12 mt-2"> </div> <div class="col-lg-12 mt-2"> <p class="submitFormHelp alert alert-info">I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.</p> </div> </div> <div class="col-lg-12 col-xl-3" id="itemInformationsDiv"> <div id="_line" > <div class="accordion" id="accordion_"> <div class="accordion-item"> <h5 class="accordion-header" id="heading_"> <button class="accordion-button bg-info bg-opacity-25 collapsed" type="button" data-bs-toggle="collapse" data-bs-target="#collapse_" aria-expanded="false" aria-controls="collapse_"><i class="fas fa-info-circle"></i> Informazioni</button> </h5> <div id="collapse_" class="accordion-collapse collapse show" aria-labelledby="heading_" data-bs-parent="#accordion_"> <div class="accordion-body"> Utilizza questo identificativo per citare o creare un link a questo documento: <code>https://hdl.handle.net/11384/85931</code> </div> </div> </div> </div> </div> <script type="text/javascript"> runningExternal=false; </script> <div class="card border-white mt-2" > <div class="card-header bg-white text-primary"><h5>Citazioni</h5></div> <ul class="list-group list-group-flush"> <li class="list-group-item d-flex justify-content-between align-items-start"> <a href="#" ><img src="https://ricerca.sns.it/sr/cineca/images/thirdparty/pmc_small.png" style="height: 18px;" alt="???jsp.display-item.citation.pmc???"/></a> <span class="badge bg-secondary rounded-pill" data-bs-toggle="tooltip" data-bs-placement="left" id="pmcCitedResultTotal" title="" >ND</span> </li> <script type="text/javascript"> var pmcChartData = []; pmcChartData[0] = 0; pmcChartData[1] = 0; pmcChartData[2] = 0; pmcChartData[3] = 0; pmcChartData[4] = 0; pmcChartData[5] = 0; function pmcUpdateCitationQueue(forceUpdate) { //console.log('call pmcUpdateCitation'); if (runningExternal) { var rnd=Math.floor(Math.random() * (2000 + 1) + 1000); //console.log('wait pmcUpdateCitation for '+rnd); 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role="status"></div>'); $.ajax({ url: '/itemExternalCitation/isi/get.json', dataType: 'json', data: { discriminator: 'isi', itemId: 'e3aace00-b9f4-4c98-e053-3705fe0acb7e', forceUpdate: forceUpdate } }).done(function(adata) { $('#isiCitedResultTotal').tooltip('dispose'); $('#isiCitedResultTotal').prop("onclick", null).off("click"); if (adata.total==null){ $('#isiCitedResultTotal').html('ND'); } else { $('#isiCitedResultTotal').html(adata.total); } var year=new Date().getFullYear(); isiChartData[0] = (adata.yearTotalMap[''+(year-5)]!=null ? adata.yearTotalMap[''+(year-5)] : 0); isiChartData[1] = (adata.yearTotalMap[''+(year-4)]!=null ? adata.yearTotalMap[''+(year-4)] : 0); isiChartData[2] = (adata.yearTotalMap[''+(year-3)]!=null ? adata.yearTotalMap[''+(year-3)] : 0); isiChartData[3] = (adata.yearTotalMap[''+(year-2)]!=null ? adata.yearTotalMap[''+(year-2)] : 0); isiChartData[4] = (adata.yearTotalMap[''+(year-1)]!=null ? adata.yearTotalMap[''+(year-1)] : 0); isiChartData[5] = 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Si ricorda che il superamento dei valori soglia (almeno 2 su 3) 猫 requisito necessario ma non sufficiente al conseguimento dell'abilitazione.<br/>La simulazione si basa sui dati IRIS e sugli indicatori bibliometrici alla data indicata e non tiene conto di eventuali periodi di congedo obbligatorio, che in sede di domanda ASN danno diritto a incrementi percentuali dei valori. La simulazione pu貌 differire dall'esito di un鈥檈ventuale domanda ASN sia per errori di catalogazione e/o dati mancanti in IRIS, sia per la variabilit脿 dei dati bibliometrici nel tempo. Si consideri che Anvur calcola i valori degli indicatori all'ultima data utile per la presentazione delle domande.<br/><br/>La presente simulazione 猫 stata realizzata sulla base delle specifiche raccolte sul tavolo ER del Focus Group IRIS coordinato dall鈥橴niversit脿 di Modena e Reggio Emilia e delle regole riportate nel DM 589/2018 e allegata Tabella A. Cineca, l鈥橴niversit脿 di Modena e Reggio Emilia e il Focus Group IRIS non si assumono alcuna responsabilit脿 in merito all鈥檜so che il diretto interessato o terzi faranno della simulazione. 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Design of a versatile nanoparticle-based delivery system for intracellular and in vivo-targeted protein replacement therapy