The　synergistic　anti-tumor　therapy　based　on　chemotherapeutic　drugs　and　gene　drugs　has　become　a　new　direction　of　tumor　treatment.　However,　the　significantly　distinct　physicochemical　properties　and　the　unbalanced　coordinate　proportion　of　chemotherapeutic　and　genetic　drugs　limit　the　actual　therapeutic　efficiency　of　the　combined　drug　delivery　strategy.　Herein,　we　developed　a　simple　method　to　self-assemble　the　fluorine　atom-modified　antisense　oligonucleotide　(2′F-G1319)　with　chemotherapeutic　pirarubicin　(THP)　to　form　the　carrier-free　nanomedicines　(2′F-G1319/THP　NMs),　which　could　efficaciously　achieve　the　synergistic　gene　therapy　and　chemotherapy.　In　this　study,　2′F-G1319　and　THP　could　be　self-assembled　to　form　uniform　nanoparticles　through　enhanced　intermolecular　interactions　after　G1319　was　modified　with　the　fluorine　atom.　Both　in-vitro　and　in-vivo　experiments　verified　that　2′F-G1319/THP　NMs　exhibited　significant　synergistic　anti-tumor　effects　with　high　biostability　and　biocompatibility.　Owing　to　the　simple　and　universal　synthesis　process,　our　constructed　self-assembled　nanomedicine　provides　a　promising　opportunity　for　the　wide　applications　of　nanomedicines　and　is　expected　to　realize　more　effective　synergistic　anti-tumor　therapy　without　the　addition　of　non-therapeutic　excipients　©　2023　The　Authors