Iron is an essential element in almost all living organisms, including bacteria, and serves as an enzymatic cofactor to catalyze a variety of biological processes [1, 2, 3]. However, despite its abundance, the bioavailability of iron is limited due to its tendency to form insoluble Fe(III) complexes under aerobic conditions [4,5]. Poor solubility of iron is a significant challenge for bacteria, especially in iron-poor environments such as the human body, marine habitats, or soil. Bacteria have evolved sophisticated iron acquisition systems. One of the most prominent strategies is the production, secretion, and uptake of siderophores [6] (Figure 1).

Siderophores are small molecules with high iron chelating affinity. These molecules bind tightly to Fe(III), effectively solubilizing Fe(III) and facilitating its uptake into bacterial cells through specific receptor-mediated transport pathways. Bacteria can utilize siderophores to scavenge every possible iron source from their surroundings, including host transferrin and lactoferrin during infections by pathogenic bacteria [7]. By deploying and acquiring siderophores, bacteria can thrive in iron-limited environments and hosts, increasing their survival advantage.

Siderophore secretion and uptake differ between Gram-positive and Gram-negative bacteria due to variations in their cell envelope structures [6,8]. In Gram-negative bacteria, siderophores are synthesized in the cytoplasm and then transported across the inner membrane by specific transporters. They are subsequently secreted through the outer membrane using specialized proteins, such as the TolC family [9] (Figure 1a). In contrast, Gram-positive bacteria, which lack the outer membrane, secrete siderophores directly from the cytoplasm into the extracellular space (Figure 1b). Once secreted siderophores are iron-bound and transported back into bacterial cells, bacteria employ various mechanisms to release iron. One common approach is the reduction of Fe(III) to Fe(II) by cytoplasmic iron reductases. Compared with Fe(III), which is a hard Lewis acid, Fe(II) is a relatively soft Lewis acid that binds to siderophores with lower affinity, causing iron release [10]. Alternatively, some bacteria produce enzymes that hydrolyze the backbones of siderophores, by which their preorganized multiple chelating moieties fall apart, losing high iron affinity and consequently liberating iron [10] (Figure 1).

Siderophores can be conjugated with functional molecules, such as drugs or imaging agents, serving as vectors (Figure 2a). When bacteria take up siderophore conjugates, the attached functional molecules enter cells simultaneously. Thus, utilizing the iron-siderophore uptake system is a promising delivery approach [11, 12, 13, 14, 15]. Here, recent advances in their applications are summarized.