Bleomycin Loaded Fe(III)-TA@HA Nanoplatform: Enabling Photoacoustic Imaging-Guided Intralymphatic Injection and Synergistic Photothermal-Sclerosis Therapy against Lymphatic Malformations

Abstract Lymphatic malformations (LMs), particularly intractable subtypes with diffuse growth, pose significant clinical challenges due to incomplete resection, high recurrence rate, and adverse effects of conventional therapies such as sclerotherapy with bleomycin (BLM). Herein, we developed a multifunctional metal-polyphenol nanoplatform through hyaluronic acid (HA) matrix-regulated biomineralization of Fe3+ and polyphenolic tannic acid (TA), followed by loading with Bleomycin (Fe(Ⅲ)-TA/BLM@HA). This nanoassembly integrates photoacoustic (PA) imaging guidance, targeted delivery, and synergistic photothermal-sclerosis therapy against LMs. The Fe(Ⅲ)-TA/BLM@HA nanoassemblies can specifically target lymphatic endothelial cells (LECs) via HA-LYVE-1 interaction. The nanoassemblies exhibit excellent colloidal stability, remarkable photothermal conversion, and strong PA signals for real-time guided precise intralymphatic injection. Fe(Ⅲ)-TA/BLM@HA binds lymphatic endothelial cells (LECs) in a concentration-dependent manner, and exerts synergistic cytotoxicity, outperforming free BLM and Fe(Ⅲ)-TA@HA. In Balb/c mouse LM models, PA imaging visualized the spatiotemporal distribution of Fe(Ⅲ)-TA/BLM@HA post percutaneous injection. Notably, Fe(Ⅲ)-TA/BLM@HA plus 650 nm NIR laser raised lesion temperature by 13.6 °C, resolving LMs in 1–2 cycles vs 3–4 cycles for free BLM. This study confirms Fe(Ⅲ)-TA/BLM@HA as a safe, effective option for intractable LMs, with substantial translational potential for vascular anomaly management.