The　increased　prevalence　of　obesity　is　recognized　as　a　serious　public　health　problem　affecting　millions　of　people.　Although　some　anti-obesity　drugs　are　currently　licensed　for　use,　these　drugs　involve　diverse　side　effects　such　as　diarrhea,　vomiting,　and　low　efficiency.　Here　we　developed　a　safe　and　efficient　biomaterials-based　anti-obesity　nanosystem　(PCG-EPL/miR33agonist),　which　was　formed　with　poly　(citric　acid)-glycerol-polylysine　(PCG-EPL)　and　miR33　agonist　by　self-assembly.　The　PCG-EPL　could　efficiently　load,　protect　and　deliver　the　miR33　agonist　into　the　adipocytes　and　decreased　the　obesity-related　IL-1β　expression　in　adipocytes　in　vitro.　The　high-fat　diet　induced　obese　rat　model　experiment　showed　that　the　PCG-EPL/miR33agonist　via　caudal　vein　injection　effectively　reduced　the　body　weight　by　enhancing　lipid　metabolism　and　decreasing　the　inflammatory　factors　expressions　(IL-1β,　TNF-α　and　IL-6)　in　vivo,　without　suppressing　the　appetite　of　rat.　Compared　with　the　obese　mice,　mice　in　PCG-EPL/miR33　had　higher　average　food　intake　but　lower　energy　conversion　rate.　PCG-EPL/miR33agonist　significantly　inhibited　the　growth　of　adipocytes.　Noteworthy,　this　weight　loss　strategy　is　not　only　safe　and　efficient,　but　also　does　not　need　diet　control.　Thus,　PCG-EPL　may　serve　as　an　ideal　platform　for　RNA　drug　delivery　in　anti-obesity　therapy,　especially　for　those　who　need　to　lose　weight　but　unable　to　autonomously　control　their　diet.　©　2020　Elsevier　B.V.