Table 3.

Comparison of trends seen in stimuli-responsive MSNs.

Systems	Photo-Responsive	Redox-Responsive	pH-Responsive	Temperature- Sensitive	Multi-Stimuli-Responsive
Key features of system	Used as a spatio-temporal control function for cargo release. Allows for photo-guided dual therapy or simultaneous photodynamic therapy (increases ROS and photocoagulation)	Responds to raised intracellular levels of reactive oxygen species or redox fluctuations	Responsive to acidic-basic shifts, typically with the use of gating molecules that undergo conformational change with protonation.	Sensitive to change in temperature from LCST to body temperature. MSNs designed may be used for thermal ablation of cancer cells/plaque.	Designed to respond to two or more stimuli that may be either endogenous, exogenous or a combination of both. Typical linkers may use cancer cell features to enhance internalization.
Types of gating material used	Azobenzene derivatives, spiropyrans,	Thioketal species, double disulfide linker molecules	Inorganic polymers- Schiff base sensitive linkers, organic polymers- chitosan	Inorganic polymers such as PBLG or polyurethane derivatives	Conjugated polymers e.g., double disulfide linker joined to the organic chitosan.
Mentions in the literature: 2018–2020 *	GScholar: 1240 Elsevier: 181 MDPI: 22	GScholar:13,000 Elsevier: 203 MDPI: 2	GScholar: 17,100 Elsevier: 1219 MDPI: 44	GScholar:16,300 Elsevier: 1602 MDPI: 16	GScholar:14,500 Elsevier: 483 MDPI: 2
Clinical application and outcomes	2 trials recruiting 2 trial completed: Silica-gold NPs/silica-gold iron NP activated by NIR radiation saw significant regression of treated atherosclerosis. Trial 2 used sNPs for real-time imaging of nodal metastases. [128,129] 1 trial terminated Clinical trial data shows promising results; however there is a need for long-term development and prolonged testing.	-	-	-	1 trial completed: magnetic guided silica-gold NP treated atherosclerosis [130]. 1 trial terminated Long-term studies required for continuance of results obtained. However, results show developed NPs performed better than conventional treatment options giving patients a better quality of life.
Notable features that require development	Light radiation used may either have adverse effects, or have difficulty in penetrating deep layers of tissue.	Redox concentrations are subject to fluctuation, especially when targeting subcellular components. Accumulation may be seen in non-targeted tissue such as lungs, liver and spleen.	Low loading efficiency of drugs and genes. Difficulty in controlling the loading and release of bioactive molecules, as electrostatic effects are continually fluctuating. Accumulation may be seen in non-targeted tissue such as lungs, liver and spleen.	Temperature fluctuates within tissues and is also affected by environmental factors. May require an applied stimulus. Requires gating material with high thermal stability. Thermal ablation may affect changes in surrounding tissue. Further translation is required.	Although developed systems combine responsiveness to applied stimuli, there is also the possibility of a combination of barriers that may affect the NPs performance in vivo.

* Google Scholar: 2018–2020 All results, Elsevier: Research articles only (Mentions in article, abstract, or keywords), MDPI: All results.