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Background: The design of novel nanoparticles with higher therapeutic efficacy and lower side effects, is still difficult but encouraging in cancer therapy. Specifically, for upconversion nanoparticles (UCNP)-based drug release, a high intensity of NIR light (1.4~5.0 W/cm 2 ) above the maximum permissible exposure (0.33 W/cm 2 for 980 nm) is commonly used and severely limits its practical application. Methods: The highly emissive UCNP is first synthesized and then coated with mesoporous silica (MS) shell (UCMS). Next, the surface of UCMS is modified with the thioether (-S-BP) linker, leading to UCMS-S-BP nanoparticles. Finally, after the drug doxorubicin (Dox) is loaded into the pore channels of UCMS, the pore openings are blocked by the β -cyclodextrin ( β -CD) gatekeeper through the association with the -S-BP linker (UCMS(Dox)-S-BP@ β -CD). Results: Upon 980 nm NIR light irradiation with an ultralow intensity of 0.30 W/cm 2 , it is found that the loaded Dox can be released through the cleavage of thioether linkers triggering dissociation of β -CD gatekeepers. The in vitro results exhibited significantly therapeutic efficacy with 85.2% of HeLa cells killed in this study. Conclusions: An ultralow-intensity NIR light triggered on-demand drug release system has been developed by employing highly emissive UCNP and photocleavable linker with low bond dissociation energy to avoid the potential photodamage on healthy neighbor cells.

international journal of nanomedicine

&lt;p&gt;Ultralow-intensity NIR light triggered on-demand drug release by employing highly emissive UCNP and photocleavable linker with low bond dissociation energy&lt;/p&gt;