{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T21:24:17Z","timestamp":1790717057019,"version":"4.1.0"},"reference-count":197,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T00:00:00Z","timestamp":1763683200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Intracellular targeting is the missing dimension in contemporary oncology, and nanosecond pulsed electric fields (nsPEFs) uniquely aim to deliver it. By charging membranes on sub-microsecond timescales, nsPEF bypasses plasma-membrane shielding to porate organelles, collapse mitochondrial potential, perturb ER calcium, and transiently open the nuclear envelope. This mechanism reprograms malignant fate while preserving tissue architecture. This review synthesizes the most recent evidence to frame nsPEF as a programmable intracellular therapy, mapping mechanistic design rules that link pulse width, amplitude, repetition, and rise time to specific organelle responses. We outline therapeutic applications, including the induction of apoptosis in resistant tumors, immunogenic cell death with systemic memory, and synergy with checkpoint blockade. We also survey integrations with nanoparticles, calcium, and chemotherapeutic drugs for improved outcomes. We critically appraise safety, selectivity, and scalability, distill translational bottlenecks in dosimetry and standardization, and propose an actionable roadmap to accelerate clinical adoption. Viewed through this lens, nsPEF is not merely another ablation tool but a platform for precision intracellular oncotherapy, capable of drug-sparing efficacy and immune convergence when engineered with rigor.<\/jats:p>","DOI":"10.3390\/ijms262311268","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T12:41:58Z","timestamp":1763728918000},"page":"11268","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Nanosecond Pulsed Electric Fields (nsPEFs) for Precision Intracellular Oncotherapy: Recent Advances and Emerging Directions"],"prefix":"10.3390","volume":"26","author":[{"given":"Kainat","family":"Gul","sequence":"first","affiliation":[{"name":"Department of Botany, Hazara University, Mansehra 21120, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9506-5808","authenticated-orcid":false,"given":"Sohail","family":"Mumtaz","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering, Gachon University, 1342 Seongnamdaero, Sujeong-gu, Seongnam-si 13120, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"136","DOI":"10.3390\/cells2010136","article-title":"Induction of Cell Death Mechanisms and Apoptosis by Nanosecond Pulsed Electric Fields (NsPEFs)","volume":"2","author":"Beebe","year":"2013","journal-title":"Cells"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Butkus, P., Murauskas, A., Tolvai\u0161ien\u0117, S., and Novickij, V. 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