Pulsatile sequential drug release system for cascade tumor deep penetration and differentiation therapy to enhance chemoimmunotherapy.

Cancer stem cells (CSCs) and myeloid-derived suppressor cells (MDSCs) contribute to chemoresistance and immunosuppression, constraining chemoimmunotherapy outcomes. Differentiation therapy, aiming to mature CSCs and MDSCs, shows great promise. However, its efficacy is hindered by limited accessibility in hypoxic deep tumor regions. Inspired by the apoptotic body (ApoBD)-mediated deep tumor penetration, we design a pulsatile sequential drug release system with a core-shell structure. The reversible acid-responsive shell protonates and swells in lysosomes to release doxorubicin, inducing lysosomal escape and cell apoptosis. In ApoBDs, it deprotonates and contracts to prevent excessive drug release. After deep penetration via ApoBDs, the hypoxia-responsive core releases all-trans retinoic acid to reverse CSCs and MDSCs, overcoming chemoresistance and modulating the immuno-microenvironment. This strategy targets the heterogeneous distribution of CSCs and MDSCs in solid tumors, enhancing chemo-intervention and immune checkpoint blockade therapy while presenting encouraging potential for cascade deep tumor penetration and differentiation therapy.