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Tumour-associated macrophages (TAMs) represent an attractive cell target for anticancer therapy. However, selective and efficient targeting of TAMs remains difficult. Here, we constructed a novel dually functionalised nanoparticle platform ( s -T pep -NPs) by surface co-modification of nanoparticles (NPs) with tuftsin (T pep ) and legumain protease-sheddable polyethylene glycol 5k (PEG 5k ) to achieve selective targeted delivery to TAMs. The fluorescence resonance energy transfer experiment and  in vitro  cellular uptake assay confirmed that  s -T pep -NPs can responsively shed PEG 5k  and transform into active T pep -NPs upon the cleavage of legumain that is overexpressed on TAM surfaces, which then promotes TAM phagocytosis through Fc receptor-mediated pathways. Owing to the shielding effect by legumain-sheddable PEG 5k ,  s -T pep -NPs can effectively decrease the T pep -induced non-specific accumulation in mononuclear phagocyte system (MPS) organs during systemic circulation. Moreover,  s -T pep -NPs can significantly enhance the tumoural accumulation and improve the specificity and efficiency of targeting to TAMs, as compared with both controls of T pep -NPs and non-sheddable  ns -T pep -NPs. Overall, this study provides a robust nanoplatform with a novel avenue for improved selectivity of targeted delivery to TAMs.

Legumain protease-sheddable PEGylated, tuftsin-modified nanoparticles for selective targeting to tumour-associated macrophages