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  <front>
    <journal-meta>
      <journal-id journal-id-type="iso-abbrev">Pharmacophore</journal-id>
      <journal-id journal-id-type="publisher-id">pharmacophorejournal.com</journal-id>
      <journal-id journal-id-type="publisher-id">Pharmacophore</journal-id>
      <journal-title-group>
        <journal-title>Pharmacophore</journal-title>
      </journal-title-group>
      <issn pub-type="epub">2229-5402</issn>
    </journal-meta>
    <article-meta>
      <article-id pub-id-type="publisher-id">pharmacophorejournal.com-6937</article-id>
      <article-id pub-id-type="doi">10.51847/4YlxCn8KFc</article-id>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Original research</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>Co-Designing mRNA Cargo and Lipid Nanoparticles across Sequence Function, Intracellular Trafficking, Biodistribution, and Manufacturabil</article-title>
      </title-group>
                    <contrib-group>
                      <contrib contrib-type="author">
              <name>
                <surname>Ali</surname>
                <given-names>Hassan</given-names>
              </name>
                              <xref rid="aff1" ref-type="aff">1</xref>
                                                            <xref rid="cor1" ref-type="corresp" />
                          </contrib>
                      <contrib contrib-type="author">
              <name>
                <surname>Farooq</surname>
                <given-names>Mariam</given-names>
              </name>
                              <xref rid="aff1" ref-type="aff">1</xref>
                                        </contrib>
                      <contrib contrib-type="author">
              <name>
                <surname>Shah</surname>
                <given-names>Usman</given-names>
              </name>
                              <xref rid="aff2" ref-type="aff">2</xref>
                                        </contrib>
                      <contrib contrib-type="author">
              <name>
                <surname>Khan</surname>
                <given-names>Bilal</given-names>
              </name>
                              <xref rid="aff3" ref-type="aff">3</xref>
                                        </contrib>
                      <contrib contrib-type="author">
              <name>
                <surname>Malik</surname>
                <given-names>Sana</given-names>
              </name>
                              <xref rid="aff4" ref-type="aff">4</xref>
                                        </contrib>
                  </contrib-group>
                  <aff id="aff1">
            <label>1</label>Department of mRNA–LNP Co-Design and Sequence Function, Faculty of Pharmacy, University of Agriculture Faisalabad, Faisalabad, Pakistan.
          </aff>
                  <aff id="aff2">
            <label>2</label>Department of Intracellular Trafficking and Biodistribution, Faculty of Pharmacy, National University of Sciences and Technology, Islamabad, Pakistan.
          </aff>
                  <aff id="aff3">
            <label>3</label>Department of Manufacturability and Process Design, Faculty of Pharmacy, University of Punjab, Lahore, Pakistan.
          </aff>
                  <aff id="aff4">
            <label>4</label>Department of Co-Design and Therapeutic Translation, Faculty of Pharmacy, University of Karachi, Karachi, Pakistan.
          </aff>
                          <author-notes>
            <corresp id="cor1">
              <bold>Address for correspondence:</bold> Prof. Wael Abu Dayyih, Department of
              Pharmaceutical Chemistry, Faculty of Pharmacy, Mutah University, Al-Karak 61710, Jordan.
                              E-mail: <email xlink:href="hassan.ali@uaf.edu.pk">hassan.ali@uaf.edu.pk</email>
                          </corresp>
          </author-notes>
                    <pub-date pub-type="epub">
        <day>28</day>
        <month>08</month>
        <year>2026</year>
      </pub-date>
      <volume>17</volume>
      <issue>4</issue>
      <fpage>71</fpage>
      <lpage>82</lpage>
      <permissions>
        <copyright-statement>
          Copyright: &#x000a9; 2026 Pharmacophore
        </copyright-statement>
        <copyright-year>2026</copyright-year>
        <license>
          <ali:license_ref xmlns:ali="http://www.niso.org/schemas/ali/1.0/"
            specific-use="textmining" content-type="ccbyncsalicense">
            https://creativecommons.org/licenses/by-nc-sa/4.0/</ali:license_ref>
          <license-p>This is an open access journal, and articles are distributed under the terms of
            the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows
            others to remix, tweak, and build upon the work non-commercially, as long as appropriate
            credit is given and the new creations are licensed under the identical terms.</license-p>
        </license>
      </permissions>
      <abstract>
        <title>A<sc>BSTRACT</sc></title>
        <p>Messenger RNA therapeutics depend on a coupled molecular and delivery system in which sequence design, chemical composition, particle assembly, intracellular trafficking, tissue exposure, and manufacturing conditions jointly shape performance. Yet development programs commonly optimize cargo and lipid nanoparticles in partially separated workflows, often privileging a single readout such as expression, uptake, or encapsulation. This article addresses that fragmentation by proposing an original mRNA–lipid nanoparticle co-design architecture that treats the cargo, carrier, process, biological context, and therapeutic objective as interacting design states rather than independent modules. The approach is a theory-building synthesis of recent pharmaceutical, bioengineering, and computational evidence, organized around causal uncertainty, multiobjective trade-offs, and staged validation. The central contribution is a proposed architecture in which sequence–function relationships, innate-immune effects, lipid composition, particle formation, endosomal escape, biodistribution, and manufacturability are connected through explicit intermediate states and feedback loops. The architecture distinguishes predictive ranking from experimental confirmation, particle uptake from productive cytosolic delivery, organ exposure from target-cell function, and laboratory feasibility from scalable pharmaceutical control. It further argues that no universal optimum exists across vaccination, protein replacement, gene editing, immune modulation, and ex vivo engineering because each context assigns different weights to expression kinetics, inflammatory signaling, targeting, durability, safety, and process robustness. The proposal is not an empirically validated model, regulatory framework, or operational decision tool. Its value is to provide a disciplined structure for designing experiments, integrating heterogeneous evidence, reporting uncertainty, and preventing locally optimized cargo or formulation choices from being mistaken for a therapeutically and manufacturably coherent product.</p>
      </abstract>
      <kwd-group>
                <kwd>MRNA sequence design</kwd>
                <kwd>Lipid nanoparticles</kwd>
                <kwd>Endosomal escape</kwd>
                <kwd>Innate immunity</kwd>
                <kwd>Biodistribution</kwd>
                <kwd>Pharmaceutical manufacturability</kwd>
              </kwd-group>
    </article-meta>
  </front>
</article>