Peptide-dendrimer conjugates target and destruct neutrophil extracellular traps to block tumor metastasis.

Neutrophil extracellular traps (NETs) may facilitate metastasis of tumor cells through interaction with the CCDC25 located along cell membrane, resulting high mortality of patients. Although cationic materials can destruct NETs and inhibit tumor metastasis, they lack targeting ability in physiological environments. Herein, we designed and synthesized a peptide-dendrimer conjugates, AAPVRnS(5-n)-G2.5, that may target neutrophil elastase (NE), a component of NETs, expose their cationic cores by NE degradation, and finally neutralize DNAs of NETs via charge interaction. It combined a triple strategy: the AAPV tetrapeptide sequence provides targeting ability to NET-enriched regions; the arginine (R) and serine (S) segment ensures DNA binding efficacy as well as biocompatibility; and the PAMAM-G2.5 dendrimer provides multivalent effect and an extended circulation. The characterization shows that AAPVRnS(5-n)- G2.5 has NET targeting and NE responsiveness, and the obtained RnS(5-n)- G2.5 after NE treatment shows an enhanced zeta potential and DNA binding ability. In turn, the cationic RnS(5-n)-G2.5 can destroy NETs, competitively block the binding between NET-DNA and CCDC25, and then inhibit NET-induced tumor cell cytoskeleton remodeling. In vivo, the conjugates prolong the circulation half-life of the materials and promote the enrichment in organs prone to metastasis. In the 4 T1 orthotopic breast cancer mouse model, AAPVR4S1-G2.5 shows the best performance, significantly reducing the level of NETs in the lung and liver, and inhibiting tumor metastasis without causing obvious toxicity. This NET targeted and NE responsive conjugate materials provide an alternative strategy for precise inhibiting tumor metastasis.