In　personalized　cancer　immunotherapy,　developing　an　effective　neoantigen　nanovaccine　with　high　immunogenicity　is　a　significant　challenge.　Traditional　nanovaccine　delivery　systems　often　require　nanocarriers,　which　can　hinder　the　delivery　of　the　neoantigen　and　cause　significant　toxicity.　In　this　study,　we　present　an　innovative　strategy　of　carrier-free　nanovaccine　achieved　through　direct　self-assembly　of　2′-fluorinated　CpG　(2′F-CpG)　with　melanoma　neoantigen　peptide　(Obsl1).　Molecular　dynamics　simulations　demonstrated　that　the　introduction　of　a　fluorine　atom　into　CpG　increases　the　noncovalent　interaction　between　2′F-CpG　and　Obsl1,　which　enhanced　the　loading　of　Obsl1　on　2′F-CpG,　resulting　in　the　spontaneous　formation　of　a　hybrid　2′F-CpG/Obsl1　nanovaccine.　This　nanovaccine　without　extra　nanocarriers　showed　ultrahigh　Obsl1　loading　up　to　83.19　wt　%,　increasing　the　neoantigen　peptide　uptake　by　antigen-presenting　cells　(APCs).　In　C57BL/6　mice　models,　we　demonstrated　the　long-term　preventive　and　therapeutic　effects　of　the　prepared　2′F-CpG/Obsl1　nanovaccine　against　B16F10　melanoma.　Immunocellular　analysis　revealed　that　the　nanovaccine　activated　innate　and　adaptive　immune　responses　to　cancer　cells.　Hence,　this　study　established　a　simple,　safe,　and　effective　preparation　strategy　for　a　carrier-free　neoantigen　nanovaccine,　which　could　be　adapted　for　the　future　design　of　personalized　cancer　vaccines　in　clinical　settings.　©　2023　American　Chemical　Society.