Stimuli-responsive　nanoagents,　which　simultaneously　satisfy　normal　tissue　clearance　and　tumor-specific　responsive　treatment,　are　highly　attractive　for　precise　cancer　theranostics.　Herein,　we　develop　a　unique　template-induced　self-assembly　strategy　for　the　exquisitely　controlled　synthesis　of　self-assembled　lanthanide　(Ln3+)　nucleotide　nanoparticles　(LNNPs)　with　amorphous　structure　and　tunable　size　from　sub-5　nm　to　105　nm.　By　virtue　of　the　low-temperature　(10　K)　and　high-resolution　spectroscopy,　the　local　site　symmetry　of　Ln3+　in　LNNPs　is　unraveled　for　the　first　time.　The　proposed　LNNPs　are　further　demonstrated　to　possess　the　ability　for　highly　efficient　loading　and　tumor-microenvironment-responsive　release　of　doxorubicin.　Particularly,　sub-5　nm　LNNPs　not　only　exhibit　excellent　biocompatibility　and　predominant　renal-clearance　performance,　but　also　enable　efficient　tumor　retention.　These　findings　reveal　the　great　potential　of　LNNPs　as　a　new　generation　of　therapeutic　platform　to　overcome　the　dilemma　between　efficient　therapy　and　long-term　toxicity　of　nanoagents　for　future　clinical　applications.　©　2022　Wiley-VCH　GmbH