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Insufficient intratumoral penetration greatly hurdles the anticancer performance of nanomedicine.To realize highly efficient tumor penetration in a precisely and spatiotemporally controlled manner,far-red light-responsive nanoclusters (NCs) capable of size shrinkage and charge conversion were developed and co-administered with iRGD to synergistically improve the intratumoral penetration and the anticancer efficacy.The NCs were constructed using the singlet oxygen-sensitive (SOS) polyethylene glycolpolyurethane-polyethylene glycol (PEG-(1O2)PU-PEG) triblock copolymer to encapsulate the doxorubicin (DOX)-Ioaded,chlorin e6 (Ce6)-conjugated polyamindoamine (PAMAM) dendrimer (DCD) via the double-emulsion method.Co-administration of iRGD notably increased the permeability of NCs within tumor vasculature and tumor tissues.In addition,upon far-red light irradiation (660 nm) of tumors at low optical density (10 mW/cm2),the generated 1O2 could disintegrate the NCs and release the DCD with positive surface charge and ultra-small size (～ 5 nm),which synergized with iRGD to enable deep intratumoral penetration.Consequently,the local 1O2 at lethal concentrations along with the released DOX efficiently and cooperatively eradicated tumor cells.This study provides a convenient approach to spatiotemporally promote the intratumoral penetration of nanomedicine and mediate programmed anticancer therapy.