Tumor-associated macrophages (TAMs) constitute over 50% of the number of cells within the
tumor, playing a major role in
tumor progression and invasion. Remodeling the
tumor immune microenvironment by modulating TAM polarization has been emerging as a new and promising therapeutic strategy. However, the high interstitial fluid pressure and dense extracellular matrix lead to insufficient penetration of nanosized
therapies. To overcome this dilemma, an
acid-triggered size-changeable nanoparticle (aptamer/
acid sensitive linker crosslinked DGL/
zoledronic acid, i.e.,
Apt@(DGL-ZA) n NPs) with effective
tumor distribution, extravasation, and penetration is designed. Dendrigraft poly-L-lysines (DGLs) which can induce
tumor autophagy as mimics of natural abnormal
proteins are crosslinked via a mild-
acid-responsive linker (1,6-bis(4-formylbenzoyloxy) hexane). Long circulation property and
tumor penetration are achieved simultaneously by catching DGLs in neutral pH while releasing them in the
tumor's pH, like dandelion seeds in midair. The macrophage conditioning agent
zoledronic acid (ZA) is loaded on DGLs by the charge attraction. A
Tenascin-C targeting aptamer (GBI-10) is modified onto (DGL-ZA) n NPs for a
tumor-homing effect.
Apt@(DGL-ZA) n NPs show both enhanced penetration in in vitro 3D
triple negative breast cancer spheroids and in vivo
tumor tissues. Effective macrophage regulation, enhanced
tumor autophagy, and excellent in vivo antitumor efficacy are achieved, suggesting this tactic as a significant antitumor strategy.