A pH-responsive, fluorescence-traceable core–shell nanosystem was prepared by co-encapsulating bovine serum albumin–templated Au nanoclusters and doxorubicin within ionotropically crosslinked chitosan (TPP gelation) to enhance intracellular chemotherapy delivery. Formulation screening (CS:TPP 3:1–6:1) identified an optimal composition with a hydrodynamic diameter of 145 ± 5 nm, PDI 0.18, and a surface potential of +32.4 ± 1.2 mV; TEM resolved 2.1 ± 0.3 nm clusters and uniform spherical particles. The lyophilized carriers displayed mesoporosity (SBET 42.5 m2/g; pore volume 0.15 cm3/g; mean pore size 12.4 nm). High drug incorporation was achieved (encapsulation efficiency 82.3 ± 1.4%; loading capacity 12.6 ± 0.8%). Dialysis experiments revealed gated release, with ~22% (pH 7.4) versus ~65% (pH 5.0) at 24 h and ~35% versus ~88% at 72 h; acidic kinetics followed the Korsmeyer–Peppas model (R2 = 0.985; n = 0.65). Hemolysis remained 1.2% at 100 μg/mL and 90% viability at 500 μg/mL. In MGC-803 and SGC-7901 cells, the formulation lowered 48 h IC50 from 1.85 ± 0.12 to 0.92 ± 0.08 μg/mL and from 2.10 ± 0.15 to 1.15 ± 0.10 μg/mL, respectively. Uptake quantification showed a 4 h mean fluorescence intensity of 717 a.u. versus 280 a.u. for free drug, and apoptosis increased to 59.0% (early apoptosis 35.6%) compared with 40.6% (22.1%) for free drug. Confocal imaging showed time-dependent cytoplasmic-to-nuclear redistribution with persistent cluster fluorescence, supporting tracking. Together, these results suggest that enhanced cell-surface association driven by the cationic shell, combined with endo/lysosomal acidification–triggered reler exposure while limiting premature leakage under physiological pH.
He et al. (2025) studied this question.