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Protease-Gated Programmable Fusogenic Nano-Encapsulations for Spatially Selective Targeted Delivery
Protease-Gated Programmable Fusogenic Nano-Encapsulations for Spatially Selective Targeted Delivery
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20260202105309
- ISBN
- 9798270226411
- DDC
- 610
- 저자명
- Mathur, Vineet.
- 서명/저자
- Protease-Gated Programmable Fusogenic Nano-Encapsulations for Spatially Selective Targeted Delivery
- 발행사항
- [Sl] : University of California, San Francisco, 2025
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2025
- 형태사항
- 126 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 87-06, Section: B.
- 주기사항
- Advisor: Renslo, Adam R.;Jun, Young-Wook.
- 학위논문주기
- Thesis (Ph.D.)--University of California, San Francisco, 2025.
- 초록/해제
- 요약Targeted intracellular delivery remains limited by poor the rate-limiting nature of endosomal escape for most lipid nanoparticles. We developed enzyme-triggered Fusogenic Nano Encapsulations (eFugene), a protease-gated, membrane-fusogenic nanoencapsulation that converts local proteolysis into a switch that drive cell selective rapid delivery. eFugene operates through a peptide-gated interfacial charge switch, maintaining an mildly anionic "off" state in off-target environments that limit uptake while rapidly unmasking a fusogenic core that drives plasma-membrane merger and direct cytosolic release near target microenvironments. Using high-throughput, on-particle peptide screening enabled by rapid TCO-tetrazine coupling, we optimized eFugene to tune activity to the urokinase plasminogen activating system (uPA) via uPA-responsive surface (denoted u-eFugene). In 2D cocultures, u-eFugene showed a selectivity between uPA-high and uPA-low contexts and defined an operational window. In a TME-mimetic interface assay, delivery localized to tumor spheroids while polarized epithelium remained largely unlabeled, supporting spatially restricted cellular level selectivity. In 3D spheroids, u13-eFugene delivered faster and more payload than an endocytic LNP comparator (5.1x faster initial uptake; 3.81x more payload). Loading the topoisomerase I inhibitor exatecan translated these advantages into functional effects: rapid DNA damage in target cells while minimizing effect on off-target cells and a 65-fold therapeutic window, with accelerated DNA damage and increased killing in 3D tumor spheroids relative to LNP.
- 일반주제명
- Bioengineering
- 일반주제명
- Pharmaceutical sciences
- 일반주제명
- Chemistry
- 일반주제명
- Pharmacology
- 일반주제명
- Biochemistry
- 키워드
- Drug delivery
- 기타저자
- University of California, San Francisco Chemistry and Chemical Biology
- 기본자료저록
- Dissertations Abstracts International. 87-06B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
008260126s2025 us c eng d■001000017360133
■00520260202105309
■006m o d
■007cr#unu||||||||
■020 ▼a9798270226411
■035 ▼a(MiAaPQ)AAI32283987
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a610
■1001 ▼aMathur, Vineet.
■24510▼aProtease-Gated Programmable Fusogenic Nano-Encapsulations for Spatially Selective Targeted Delivery
■260 ▼a[Sl]▼bUniversity of California, San Francisco▼c2025
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2025
■300 ▼a126 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 87-06, Section: B.
■500 ▼aAdvisor: Renslo, Adam R.;Jun, Young-Wook.
■5021 ▼aThesis (Ph.D.)--University of California, San Francisco, 2025.
■520 ▼aTargeted intracellular delivery remains limited by poor the rate-limiting nature of endosomal escape for most lipid nanoparticles. We developed enzyme-triggered Fusogenic Nano Encapsulations (eFugene), a protease-gated, membrane-fusogenic nanoencapsulation that converts local proteolysis into a switch that drive cell selective rapid delivery. eFugene operates through a peptide-gated interfacial charge switch, maintaining an mildly anionic "off" state in off-target environments that limit uptake while rapidly unmasking a fusogenic core that drives plasma-membrane merger and direct cytosolic release near target microenvironments. Using high-throughput, on-particle peptide screening enabled by rapid TCO-tetrazine coupling, we optimized eFugene to tune activity to the urokinase plasminogen activating system (uPA) via uPA-responsive surface (denoted u-eFugene). In 2D cocultures, u-eFugene showed a selectivity between uPA-high and uPA-low contexts and defined an operational window. In a TME-mimetic interface assay, delivery localized to tumor spheroids while polarized epithelium remained largely unlabeled, supporting spatially restricted cellular level selectivity. In 3D spheroids, u13-eFugene delivered faster and more payload than an endocytic LNP comparator (5.1x faster initial uptake; 3.81x more payload). Loading the topoisomerase I inhibitor exatecan translated these advantages into functional effects: rapid DNA damage in target cells while minimizing effect on off-target cells and a 65-fold therapeutic window, with accelerated DNA damage and increased killing in 3D tumor spheroids relative to LNP.
■590 ▼aSchool code: 0034.
■650 4▼aBioengineering
■650 4▼aPharmaceutical sciences
■650 4▼aChemistry
■650 4▼aPharmacology
■650 4▼aBiochemistry
■653 ▼aDrug delivery
■653 ▼aFusogenic drug delivery
■653 ▼aMicroenvironment responsive
■653 ▼aSwitchable platform
■653 ▼aNanoencapsulation
■690 ▼a0202
■690 ▼a0572
■690 ▼a0485
■690 ▼a0487
■690 ▼a0419
■71020▼aUniversity of California, San Francisco▼bChemistry and Chemical Biology.
■7730 ▼tDissertations Abstracts International▼g87-06B.
■790 ▼a0034
■791 ▼aPh.D.
■792 ▼a2025
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17360133▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
