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Obscurin (720\u2013870\u00a0kDa), a giant signaling protein localizing to the breast epithelial cell membrane, is a metastasis suppressor commonly lost in breast cancer. Obscurin loss upregulates the oncogenic PI3K\/Akt axis. While restoring obscurin expression is crucial from a translational standpoint, it poses major challenges due to its immense size. Herein, we overcome this hurdle by delivering a mini\u2010obscurin\u2014comprising the obscurin\u2010pleckstrin homology (PH) domain, which is \u223c50\u2010times smaller than the full\u2010length protein\u2014into aggressive breast cancer cells via adenovirus and lipid nanoparticles. Mechanistically, the obscurin\u2010PH\u2010domain interacts with the PI3K\u2010p85 regulatory subunit. Membrane\u2010targeted obscurin\u2010PH sequesters p85, suppressing PI3K\/Akt activity. p85\u2010sequestration eliminates filopodia, hampering migration and adhesion to pre\u2010metastatic niche extracellular matrix substrates. This intervention further eradicates invadopodia and reduces matrix metalloproteinase expression, blocking invasion, dissemination, and metastasis. We recapitulate this phenotype using the structurally homologous kalirin and PLC\u03b31 PH\u2010domains and ultimately uncover a family of nine PH\u2010domains that may act as PI3K inhibitors, unified by the \u201c\n                    <jats:italic>p<\/jats:italic>\n                    85\n                    <jats:italic>i<\/jats:italic>\n                    nhibitory\n                    <jats:italic>m<\/jats:italic>\n                    etastasis\n                    <jats:italic>s<\/jats:italic>\n                    uppressor\u201d (PIMS) motif, mediating this effect. This work engineers a first\u2010in\u2010class group of non\u2010chemical PI3K inhibitors, uniquely targeting the PI3K\u2010p85 subunit, galvanizing novel gene therapies for treating metastatic breast cancer.\n                  <\/jats:p>","DOI":"10.1002\/advs.202518339","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T11:47:24Z","timestamp":1774871244000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Delivery of Pleckstrin\u2010Homology Domains Suppresses PI3K\/Akt Signaling and Breast Cancer Metastasis"],"prefix":"10.1002","volume":"13","author":[{"given":"Matthew","family":"Eason","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology University of Maryland School of Medicine  Baltimore Maryland USA"},{"name":"Marlene and Stewart Greenebaum Comprehensive Cancer Center  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anindya","family":"Sen","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering The Johns Hopkins University  Baltimore Maryland USA"},{"name":"Institute For NanoBioTechnology Johns Hopkins University  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suhan","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology University of Maryland School of Medicine  Baltimore Maryland USA"},{"name":"Marlene and Stewart Greenebaum Comprehensive Cancer Center  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Se Jong","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering The Johns Hopkins University  Baltimore Maryland USA"},{"name":"Institute For NanoBioTechnology Johns Hopkins University  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keyata","family":"Thompson","sequence":"additional","affiliation":[{"name":"Marlene and Stewart Greenebaum Comprehensive Cancer Center  Baltimore Maryland USA"},{"name":"Department of Pharmacology and Physiology University of Maryland School of Medicine  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md Musavvir","family":"Mahmud","sequence":"additional","affiliation":[{"name":"Marlene and Stewart Greenebaum Comprehensive Cancer Center  Baltimore Maryland USA"},{"name":"Department of Neurosurgery University of Maryland School of Medicine  Baltimore Maryland USA"},{"name":"Fischell Department of Bioengineering A. James Clarke School of Engineering University of Maryland  College Park Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Poornima","family":"Dubey","sequence":"additional","affiliation":[{"name":"Marlene and Stewart Greenebaum Comprehensive Cancer Center  Baltimore Maryland USA"},{"name":"Department of Pharmacology and Physiology University of Maryland School of Medicine  Baltimore Maryland USA"},{"name":"Department of Neurosurgery University of Maryland School of Medicine  Baltimore Maryland USA"},{"name":"Fischell Department of Bioengineering A. James Clarke School of Engineering University of Maryland  College Park Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Talia","family":"Guardia","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology University of Maryland School of Medicine  Baltimore Maryland USA"},{"name":"Marlene and Stewart Greenebaum Comprehensive Cancer Center  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Kim","sequence":"additional","affiliation":[{"name":"Marlene and Stewart Greenebaum Comprehensive Cancer Center  Baltimore Maryland USA"},{"name":"Department of Pharmacology and Physiology University of Maryland School of Medicine  Baltimore Maryland USA"},{"name":"Department of Neurosurgery University of Maryland School of Medicine  Baltimore Maryland USA"},{"name":"Fischell Department of Bioengineering A. James Clarke School of Engineering University of Maryland  College Park Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart","family":"Martin","sequence":"additional","affiliation":[{"name":"Marlene and Stewart Greenebaum Comprehensive Cancer Center  Baltimore Maryland USA"},{"name":"Department of Pharmacology and Physiology University of Maryland School of Medicine  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan","family":"Wright","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry James Madison University  Harrisonburg Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantinos","family":"Konstantopoulos","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering The Johns Hopkins University  Baltimore Maryland USA"},{"name":"Institute For NanoBioTechnology Johns Hopkins University  Baltimore Maryland USA"},{"name":"Department of Oncology The Sidney Kimmel Comprehensive Cancer Center The Johns Hopkins University School of Medicine  Baltimore Maryland USA"},{"name":"Department of Biomedical Engineering Johns Hopkins University  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3948-1959","authenticated-orcid":false,"given":"Aikaterini","family":"Kontrogianni\u2010Konstantopoulos","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology University of Maryland School of Medicine  Baltimore Maryland USA"},{"name":"Marlene and Stewart Greenebaum Comprehensive Cancer Center  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,30]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2021.188567"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00017.2009"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.12\u2010205419"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2215553120"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.9985"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.2338"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.20404"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2014.358"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2020.06.015"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010021\u201000828\u20105"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22010173"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.3892\/ijo.2013.1992"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0128365"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.151.2.249"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010018\u201003571\u20108"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2002964"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/dvg.20203"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0902369106"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1055\/s\u20100034\u20101376977"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.82700"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2017.6"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41698-018-0047-0"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2009.25.9820"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/4578373"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.15.4.1942"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm11051250"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.11.037"},{"key":"e_1_2_11_29_1","article-title":"MMP1 expression Is Activated by Slug and Enhances Multi\u2010drug Resistance (MDR) in Breast Cancer","author":"Ching\u2010Ju Shen Y.\u2010L. 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