and trigger their release when they reach the small intestine. Although promising hypoglycemic effects were observed with some systems, it must be noted that complete prevention of release into the stomach was not achieved and the oral formulation did not show the same efficacy as SC insulin, even when administered at higher doses (30 IU kg -1 vs 5 IU kg -1 , respectively). Changes in environmental pH can also be advantageous for the controlled release of anticancer drugs, antimicrobial agents and efficient wound healing. For instance, the structural modification of a P(NIPAAm-co-AAm) hydrogel due to change in the copolymer hydrophobicity, allowed the selective liberation of Ag + ions, from the incorporated AgNO3 NPs, exclusively in an alkaline environment (pH > 7) within bacteria-infected wounds (Figure ). This pH-sensitive "on-off" feature has proven to be effective in eradicating clinically relevant wound infections, as demonstrated in a murine model involving multidrug-resistant S. aureus. Simultaneously, this composite hydrogel promoted wound closure, re-epithelialization, and a higher degree of collagen deposition compared to both NP-free hydrogel and Ag sulfadiazine commercial formulation. Silver was also incorporated also into MSNs subsequently embedded in a covalently crosslinked hydrogel made of PEG diacrylate and HA-DA, designed to ensure sustained retention on bacteriainfected wounds. The accelerated destabilization of MSNs in response to the acidification of the surrounding medium led to the rapid release of Ag + that effectively cleared bacteria in the vicinity of the wound, promoting tissue healing. Despite the appeal of these approaches, systems relying on endogenous triggers such as oxygen species content, pH gradients and/or the presence of enzymes, often face the obstacle of patient variability. Improving screening methods to accurately stratify patients based on these specific elements would undoubtedly maximize the advantages derived from these hybrid hydrogels. 001. Adapted with permission. Copyright 2022 American Chemical Society.