CXCR4‐Enriched Nano‐Trap Targeting CXCL12 in Lung for Early Prevention and Enhanced Photodynamic Therapy of Breast Cancer Metastasis

Abstract Breast cancer metastasis is strongly correlated with CXCR4‐CXCL12 axis, in which the CXCR4 positive cancer cells are recruited to target organs rich in CXCL12. Although various agents have been developed to inhibit CXCR4, few strategies are reported for targeting and perturbation of CXCL12 to control breast cancer metastasis. Inspired by the increasing popularity of cell membrane (CM)‐derived therapeutics, herein, CXCR4‐enriched 4T1 CMs loaded with copper‐indium‐sulfide quantum dots (QDs) nanoparticles are employed as Nano‐trap to occupy CXCL12 and block breast cancer lung metastasis. CMs fused onto QDs cores faithfully inherit CXCR4 expression of the source cells. CXCR4‐upregulated Nano‐trap binds CXCL12 protein more efficiently than the CXCR4‐silenced counterparts, which effectively abrogate CXCL12‐mediated cancer cell invasion in vitro. In vivo fluorescent imaging reveals preferential distribution of Nano‐trap in lungs with abundant CXCL12 expression. Further interrogation of the in vivo efficacy finds lung metastasis is successfully delayed in breast cancer models pre‐injected with Nano‐trap, which reduces CXCL12 exposure in lung. For the already formed lung metastasis, Nano‐trap can alleviate hypoxia by regulating alpha‐smooth muscle actin, thus improving photodynamic therapy in the metastatic tumor. This proof‐of‐concept study sheds light on exploiting more functionalities of CM proteins for metastasis management.