Tumor‐Microenvironment‐Responsive Biodegradable Nanoagents Based on Lanthanide Nucleotide Self‐Assemblies toward Precise Cancer Therapy

Abstract 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 (Ln 3+ ) 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 Ln 3+ 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.