{
  "abstract": "Efficient delivery of plasmid DNA (pDNA) into the nucleus remains a major bottleneck in nonviral gene therapy, particularly in post-mitotic and slowly dividing cells where the nuclear envelope constitutes a permanent barrier to passive entry. This review considers the two main strategies for active nuclear targeting: nuclear localisation signal (NLS) peptides, which recruit importin-α/β receptors directly to DNA cargo, and DNA nuclear targeting sequences (DTS), which exploit NLS-bearing transcription factors to mediate piggyback nuclear import. Rather than re-cataloguing nuclear import biology, we focus on the conditions under which each strategy succeeds or fails, incorporating advances in nuclear pore complex architecture and permeability, karyopherin-FG-nucleoporin electrostatics, and cytoplasmic constraints such as barrier-to-autointegration factor (BAF)-mediated clustering of exogenous DNA. NLS classes are compared with universal (SV40 enhancer), inducible (NF-κB) and tissue-specific (SMGA, SP-C, T1α) DTS elements, and four chemical coupling strategies are evaluated across peptide-, polymer- and lipid-based nanoassemblies. To address the near-absence of NLS/DTS mechanisms in current clinical pDNA programmes, we propose the Nuclear Accessibility Index (NAI): a three-axis framework integrating cell division status, carrier-DNA accessibility and intracellular signalling context. Treating the NAI as an axis vector rather than a summed score defines permissive, conditional and excluded regions of the design space. Two matter in practice: one in which highly proliferative cells render active targeting redundant, and one in which the rate-limiting problem is carrier engineering rather than the addition of a signal. The NAI offers design principles for nuclear-targeted nanocarriers and defines the preconditions for therapeutically relevant active import.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Republic of Korea.",
    "Research Center for Molecular Control for Cancer Cell Diversity, Pusan National University, Yangsan, Republic of Korea."
  ],
  "article_type": "review article",
  "arxiv": null,
  "author_total": 4,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Taegeun Lee"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Ye-Rin Kim"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Euijin Lee"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Sae-Ock Oh"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/cdawqh0bhqkbc.bib",
  "cited_by": 0,
  "doi": "10.1080/10717544.2026.2741456",
  "fulltext_url": "https://europepmc.org/articles/PMC13678880",
  "id": "cdawqh0bhqkbc",
  "issns": [
    "1071-7544",
    "1521-0464"
  ],
  "landing_url": "https://europepmc.org/article/MED/42881531",
  "language": "eng",
  "licence": "CC-BY-NC",
  "licence_label": "CC BY-NC",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|RNA Interference and Gene Delivery"
    ]
  ],
  "openalex": "W7222528543",
  "pdf_url": "https://europepmc.org/articles/PMC13678880?pdf=render",
  "pmcid": "PMC13678880",
  "pmid": "42881531",
  "published": "2026-10-15",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/cdawqh0bhqkbc.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:46Z",
      "native_id": "MED:42881531",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42881531"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|RNA Interference and Gene Delivery",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Overcoming the nuclear barrier in nonviral gene therapy: mechanisms, carrier design, and translational perspectives on NLS peptide and DNA targeting sequence strategies.",
  "title_text": "Overcoming the nuclear barrier in nonviral gene therapy: mechanisms, carrier design, and translational perspectives on NLS peptide and DNA targeting sequence strategies.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:18:46Z",
  "url": "https://research.draconitic.com/paper/cdawqh0bhqkbc",
  "venue": "Drug delivery",
  "versions": []
}