Specific Multimodal Imaging of Deep-Seated Tumor with High Intratumoral Retention <i>via In Situ</i> Assembly of Probes

The low tumor retention of nanomedicines severely limits the specificity of diagnostic imaging and the efficacy of subsequent therapies. Herein, we report a targeted zwitterionic fluoropolymer probe (PTFBPA-RGD) engineered for exceptional intratumoral retention through tumor microenvironment (TME)-triggered in situ assembly. The probe incorporates stealthy zwitterionic brushes to minimize protein adsorption and prolong systemic circulation. Upon reaching the acidic TME, hydrogen bonding between the trifluoroborate and carboxylic acid moieties acts as an adhesive, driving the self-assembly of the probe into large aggregates, thereby prolonging intratumoral retention. Leveraging its intrinsic high fluorine content, zero-background 19 F magnetic resonance imaging ( 19 F MRI) demonstrated the precise localization of deep-seated tumors across subcutaneous, orthotopic (bladder/liver), and metastatic lung models. After loading with 177 Lu, tumor accumulation peaked at 48 h and remarkably retained 82% of this peak value even 96 h postinjection, leading to robust antitumor efficacy. This work provides an effective strategy to fabricate nanoprobes with high intratumoral retention for the specific multimodal imaging and therapy of deep-seated tumors.