Purpose <p>This study set out to design and test smart pH-triggered nano-liposomal creams as a topical anti-aging treatment by co-encapsulating four natural bioactives -Silymarin, Curcumin, Resveratrol, and Vitamin C - in order to increase delivery to the skin and extend the efficacy duration and stability.</p> Method <p>Seven (F1-F7) of the formulations were prepared through thin-film hydration and probe sonication. The physicochemical characteristics of size of the vesicles, polydispersity index (PDI), zeta potential, and encapsulation efficiency were evaluated. On the basis of preliminary estimations, three formulations (F1, F3, and F6) with high fast, balanced, and sustained release rates have been chosen to undergo in vitro further characterization such as drug release experiments at pH 5.5, enzyme inhibition, antioxidant activity, cytocompatibility (MTT assay) and fibroblast migration.</p> Result <p>The sizes of the vesicles were 81–170&#xa0;nm with PDI ≤ 0.30 and zeta potentials ≤ − 26 mV, which points to homogenous and colloidal stability. It was found to have high encapsulation efficiency (&gt; 90% on hydrophobic bioactives and &gt; 80% on vitamin C). The kinetics of release were releases following the Higuchi or zero-order models and the F1 had the quickest release. F1 was also found to be better in enzyme inhibition, antioxidants, cell survival (≥ 91%), and wound healing than F3, F6, and vehicle.</p> Conclusion <p>The F1 version became a lead candidate, including rapid bioactive release, high biological activity, and high cytocompatibility, which is a promising way of pH-responsive, multi-bioactive liposomal creams in topical anti-aging therapy.</p>