Self-assembled nanoaggregates co-encapsulating doxorubicin (DOX) and oligonucleotide are prepared for dual-responsive breakdown of the nanostructure with complete disappearance characteristics. Four-arm poly(ethylene glycol) is co-conjugated with DOX and anti-bcl-2 oligonucleotide with reducible linkers and acid-cleavable linkers, respectively. The conjugate is hydrophobically self-assembled into nanoaggregates in aqueous solution. Elemental scanning of the nanoaggregates reveals their core–shell structure with DOX and oligonucleotide located at the core and the shell, respectively. The tracking of size modulation suggests the complete disappearance of the particles under reducing conditions and the liberation of oligonucleotide at low pH, which is confirmed by dynamic light scattering and electron microscopy. The release of DOX and oligonucleotide is controlled by the pH and the reducing potential of the medium, and most of the drug and DNA are released in 24 h. The released fractions are analyzed by reversed-phase chromatography, which indicates facile cleavage of DOX and oligonucleotide from the carriers. The nanoaggregates with both DOX and oligonucleotide show the lowest IC50 value when a cytotoxicity assay is performed against A549 cells. Apoptosis assay also confirms that cells treated with the nanoaggregates having both DOX and oligonucleotide show higher fluorescence intensity of antiapoptotic antibody than native DOX.