Triple-negative　breast　cancer　(TNBC)　accounts　for　approximately　15%　of　breast　cancers　and　lacks　estrogen　receptor　(ER),　progesterone　receptor　(PR),　and　human　epidermal　growth　factor　receptor　2　(HER2),　rendering　it　unresponsive　to　hormonal　or　anti-HER2　therapies.　Due　to　its　poor　prognosis　and　limited　treatment　options,　there　is　an　urgent　need　for　targeted　therapies.　In　this　study,　we　developed　highly　adaptable　polyamidoamine　(PAMAM)　dendrimer-based　gel　nanoparticles　with　dual-targeting　capabilities　against　urokinase-type　plasminogen　activator　receptor　(uPAR)　and　ribonucleotide　reductase　R2　(R2).　These　nanoparticles　were　designed　to　target　both　TNBC　cells　and　cancer-associated　stromal　cells　by　leveraging　uPA-uPAR　interactions　and　delivering　the　antisense　oligonucleotide　GTI-2040　(GTI)　against　R2.　The　resulting　dual-functional　dendrimer　gel　nanoparticles,　GDP-uPA/GTI,　demonstrated　good　biocompatibility,　with　an　average　size　of　∼16.45　nm.　GDP-uPA/GTI　enhanced　GTI　delivery　by　3.4-fold　in　TNBC　cells　(MDA-MB-231)　and　by　4.8-fold　in　stromal　cells　(HCC2218)　compared　to　GTI　alone.　It　reduced　R2　expression　by　83.1%　and　induced　∼30%　TNBC　cell　death.　In　a　TNBC　xenograft　model,　GDP-uPA/GTI　significantly　inhibited　tumor　growth　by　50.5%.　These　findings　highlight　the　unique　design　of　the　dual-functional　dendrimer　gel　nanoparticles　and　their　dual-targeting　efficacy,　demonstrating　their　potential　as　a　promising　therapeutic　strategy　for　TNBC.　©　2025　American　Chemical　Society.