Upconversion nanoparticle (UCNP)-mediated photodynamic therapy has shown great effectiveness in increasing the tissue-penetration depth of light to combat deep-seated tumors. However, the inevitable phototoxicity to normal tissues resulting from the lack of tumor selectivity remains as a major challenge. Here, the development of tumor-pH-sensitive photodynamic nanoagents (PPNs) comprised of self-assembled photosensitizers grafted pH-responsive polymeric ligands and UCNPs is reported. Under neutral pH conditions, photosensitizers aggregated in the PPNs are self-quenched; however, upon entry into a tumor microenvironment with lower pH, the PPNs not only exhibit enhanced tumor-cell internalization due to charge reversal but also are further disassembled into well-dispersed nanoparticles in the endo/lysosomes of tumor cells, enabling the efficient activation of photosensitizers. The results demonstrate the attractive properties of both UCNP-mediated deep-tissue penetration of light and high therapeutic selectivity in vitro and in vivo.

Responsive Assembly of Upconversion Nanoparticles for pH‐Activated and Near‐Infrared‐Triggered Photodynamic Therapy of Deep Tumors