Figure 1.

Schematic representation of preparation and mode of action of the tumor-targeted nanospheres. (a) The nanospheres consist of an upconversion core of sodium yttrium fluoride doped with lanthanides—ytterbium, erbium, and gadolinium—and bismuth selenide (NaYF₄:Yb/Er/Gd,Bi₂Se₃) within a mesoporous silica shell that encapsulates a photosensitizer, chlorin e6 (Ce6), in its pores. The Ce6-loaded upconversion mesoporous silica nanospheres (Ce6-UMSNs) are then “wrapped” with lipid/polyethylene glycol (DPPC/cholesterol/DSPE-PEG₂₀₀₀-maleimide). Finally, the Ce6-loaded, lipid/PEG-coated UMSNs (Ce6-LUMSNs) are functionalized with the acidity-triggered rational membrane (ATRAM) peptide. (b) In mildly acidic conditions, ATRAM inserts into lipid bilayers as a transmembrane α-helix. As the membrane insertion pK_a of ATRAM is 6.5,²³ the peptide promotes targeting of ATRAM-functionalized Ce6-LUMSNs (Ce6-ALUMSNs) to cancer cells in the mildly acidic (pH ≈ 6.5–6.8) microenvironment of solid tumors.⁷¹ (c) ALUMSNs are efficiently internalized into tumor cells, where subsequent near-infrared (NIR, 980 nm) laser irradiation of the nanospheres results in substantial cytotoxicity due to the combined effects of hyperthermia and reactive oxygen species (ROS) generation.