Precise　control　of　cargo　release　is　essential　but　still　a　great　challenge　for　any　drug　delivery　system.　Irreversible　electroporation　(IRE),　utilizing　short　high-voltage　pulsed　electric　fields　to　destabilize　the　biological　membrane,　has　been　recently　approved　as　a　non-thermal　technique　for　tumor　ablation　without　destroying　the　integrity　of　adjacent　collagenous　structures.　Due　to　the　electro-permeating　membrane　ability,　IRE　might　also　have　great　potential　to　realize　the　controlled　drug　release　in　response　to　various　input　IRE　parameters,　which　were　tested　in　a　red　blood　cell　(RBC)　model　in　this　work.　According　to　the　mathematical　simulation　model　of　a　round　biconcave　disc-like　cell　based　on　RBC　shape　and　dielectric　characteristics,　the　permeability　and　the　pore　density　of　the　RBC　membrane　were　found　to　quantitatively　depend　on　the　pulse　parameters.　To　further　provide　solid　experimental　evidence,　indocyanine　green　(ICG)　and　doxorubicin　(DOX)　were　both　loaded　inside　RBCs　(RBC@DOX&ICG)　and　the　drug　release　rates　were　found　to　be　tailorable　by　microsecond　pulsed　electric　field　(mu　sPEF).　In　addition,　mu　sPEF　could　effectively　modulate　the　tumor　stroma　to　augment　therapy　efficacy　by　increasing　micro-vessel　density　and　permeability,　softening　extracellular　matrix,　and　alleviating　tumor　hypoxia.　Benefiting　from　these　advantages,　this　IRE-responsive　RBC@DOX&ICG　achieved　a　remarkably　synergistic　anti-cancer　effect　by　the　combination　of　mu　sPEF　and　chemotherapy　in　the　tumor-bearing　mice　model,　with　the　survival　time　increasing　above　90　days　without　tumor　burden.　Given　that　IRE　is　easily　adaptable　to　different　plasma　membrane-based　vehicles　for　delivering　diverse　drugs,　this　approach　could　offer　a　general　applicability　for　cancer　treatment.　(c)　2023　Author(s).　All　article　content,　except　where　otherwise　noted,　is　licensed　under　a　Creative　Commons　Attribution　(CC　BY)　license　(http://creativecommons.org/licenses/by/4.0/)