Coating mesoporous drug carriers on the surface of persistent luminescence nanoparticles (PLNPs) not only allows continuous luminous imaging without spontaneous fluorescence interference, but also provides drug release guidance. However, in most cases, the encapsulation of the drug-loaded shells significantly reduces the luminescence of PLNPs, which is unfavorable for bioimaging. In addition, conventional drug-loaded shells alone, such as silica shells, have difficulty in achieving responsive fast drug release. Herein, we report the fabrication of mesoporous polyacrylic acid (PAA)/calcium phosphate (CaP) shell-coated PLNPs (PLNPs@PAA/CaP) for improved afterglow bioimaging and drug delivery. The encapsulation of the PAA/CaP shell effectively prolonged the decay time and enhanced the sustained luminescence of PLNPs by about three times due to the passivation of the surface defects of PLNPs by the shell, and the energy transfer between the shell and PLNPs. Meanwhile, the mesoporous structure and negative charge of the PAA/CaP shells enabled the prepared PLNPs@PAA/CaP to carry the positively charged drug doxycycline hydrochloride efficiently. Under the acidic conditions of bacterial infection, the degradation of PAA/CaP shells and the ionization of PAA enabled fast drug release for effective killing of bacteria at the infection site. The excellent persistent luminescence properties, outstanding biocompatibility, and rapid responsive release feature make the prepared PLNPs@PAA/CaP a promising nanoplatform for diagnostic and therapeutic applications.