Programmable nanocarriers with reversible ligand shielding and acid-triggered burst release for sequential tumor penetration and intracellular drug delivery.

The treatment of solid tumors with nanomedicines faces two major challenges: poor penetration of nanomedicines into deep tumor tissues and slow intracellular drug release, leading to suboptimal therapeutic efficacy. To address these issues, this study designed and constructed a programmable folate-reversibly shielded acid self-amplifying nanomedicine (sDPFP NMs) featuring reversible ligand shielding and acid-triggered burst release. This carrier utilizes hydrophobically modified dextran (sDex) as the hydrophobic core and polyethylene glycol (PEG) as the hydrophilic shell, with a hypoxia-responsive azobenzene linker connecting the PEG layer to achieve reversible shielding of the folate ligand. Through hypoxia-regulated reversible ligand shielding, enhanced penetration of the nanomedicine into solid tumors was achieved. The self-amplifying degradation of sDex under acidic conditions triggered rapid burst release of doxorubicin within tumor cells. Results demonstrated that sDPFP NMs exhibit excellent tumor penetration and outstanding anti-tumor efficacy, effectively overcoming the bottlenecks of tumor penetration and intracellular delivery, thus providing a new strategy for solid tumor therapy.