Deep tumor access via tumor-specific mannose unmasking: Smart heptamannosylated β-cyclodextrin nanoassembly

Tumor-resident immune cells, such as tumor-associated macrophages (TAMs), possess inherent tumor-penetrating capabilities and hold significant potential for actively transporting extravasated therapeutics through dense tumor stroma to eliminate deep-seated tumor cells. Inspired by this mechanism, we engineered TAM-hitchhiking nanocarriers ("nano-hitchhikers") for deep-tumor drug delivery. The nano-hitchhikers comprise heptamannosylated β-cyclodextrin loaded with doxorubicin (Dox), crosslinked via phenylboronic acid-terminated anti-PD-L1 peptides with a diameter of ∼100 nm. Boronate ester formation with vicinal diols on mannose-a TAM-targeting ligand-rendered the nano-hitchhikers inert during systemic circulation. Upon accumulation in the acidic tumor microenvironment, acid-triggered hydrolysis of boronate esters exposed mannose, enabling active TAM hitchhiking. Subsequently, TAM-mediated transport delivered Dox into deep tumor regions in a time-dependent manner, reaching a deep-penetration at 24 h post-i.v. injection. Subsequently, the Dox released from TAMs elicited potent cytotoxicity and robust immunogenic cell death. When synergized with the in situ released anti-PD-L1 peptides, the anti-tumor efficacy reached 43.4% in the 4T1 model. Additionally, this deep-delivery strategy successfully reprogrammed the immunosuppressive microenvironment, evidenced by a 3-fold increase in CD8⁺ T cell infiltration and markedly enhanced dendritic cell maturation (46.7 ± 0.76%). Ultimately, this chemo-immunotherapy achieved significant tumor growth inhibition in the 4T1 model, alongside robust therapeutic efficacy in the stroma-rich Pan02 model. Our work presents an in situ activable system leveraging endogenous immune cells for precision eradication of deep tumors.