The continued ravages of multidrug-resistant (MDR) bacteria threaten public health and food security (Breidenstein et al., 2011, Das et al., 2020, Medina and Pieper, 2016, Stevenson, 2023, Zhang et al., 2020b). Recent clinical data indicate that patients with sepsis induced by MDR bacteria survive the initial inflammatory storm but rapidly progress to a prolonged immunosuppressive state. This condition is characterized by immune cell paralysis and death, resulting in an inability to eliminate invading pathogens, increased vulnerability to hospital-acquired infections, and high mortality rates (Hotchkiss et al., 2013, Otto et al., 2011). Antibiotic therapy was the standard treatment in sepsis clinical guidelines; however, a significant rise in the overall mortality rate of MDR-bacteria-induced sepsis has underscored the urgency of antibiotic resistance and the scarcity of effective antimicrobial agents (Pallavali et al., 2017). The scarcity of effective antimicrobial agents has led to a rise in alternative therapies, such as antimicrobial peptides, an ancient weapon of the immune system against invasive pathogens, which has regained popularity (Dou et al., 2023, Li et al., 2023, Yang et al., 2023).

Since the early 1920s, some non-ribosomally synthesized peptides or proteinaceous substances, also known as "peptide antibiotics" with antibacterial and antifungal activity, were isolated from a variety of prokaryotes (Awan et al., 2017, Banko et al., 1987). Subsequently, some gene-encoded, ribosomally synthesized peptides were successively reported, such as Melittin and Bombinin (Zhong et al., 2022). Until the discovery of cecropin in silk moth (Steiner et al., 1981) and defensins in mammalian neutrophils (Selsted et al., 1985) in the 1980s, the term “antimicrobial peptides” (AMPs) was only formally proposed. During this period, AMPs research informally entered the golden period with the aim of transforming an evolutionary antimicrobial shield into the next century's antibiotic drugs. Although AMPs were initially discovered based on their antimicrobial properties, the well-optimized antimicrobial activities of most AMPs would still be suppressed by the divalent cations and polyanions (e.g., heparin) in the blood, organs, mucosa, and body fluids (Chu et al., 2013, Starr et al., 2016). This indicates that although the DBAASP database contains more than 20,000 AMPs, very few of them have completed clinical phase Ⅰ-Ⅲ trials and been commercialized as alternatives to traditional antibiotics (http://dramp.cpu-bioinfor.org/browse/ClinicalTrialsData.php). The highly conserved and ubiquitous characteristics of AMPs in the innate immune system cannot be explained by the increasing number of reports of bacterial resistance against AMPs (Abdi et al., 2019).

The challenges associated with the clinical applications of AMPs have forced researchers to reconsider the role of AMPs in the innate immune system. Recent worldwide in-depth studies have identified the immunomodulatory role of many AMPs (particularly those from mammals) rather than simply direct antibacterial activities (Hancock et al., 2016). The host-directed immunomodulatory functions of AMPs may be unaffected by physiological conditions, avoiding selective pressure for the evolution of microbial resistance (Hancock et al., 2012). Unlike other treatments only aiming at activating antibacterial immunity, AMPs can selectively activate the innate immune system without the risk of inducing hyperinflammatory states (Hancock et al., 2012, Merlini et al., 2016, Scott et al., 2007). Therefore, AMPs with immunomodulatory functions are still referred to by the more general term "host defense peptides (HDPs)", which more accurately describes their anti-infective functions (Hancock et al., 2016). Despite their considerable potential, native HDPs have limited systemic clinical applications as immunomodulatory agents due to poor absorption, biodistribution, metabolism, host toxicity, and excretion properties (Box 1) (Di, 2015, Zhang and Falla, 2009). To address these issues, the optimization and site-targeted delivery of existing HDPs, and the biomimetic design of novel peptides/peptide polymers with immunomodulatory functions (so-called immunomodulatory peptides) may increase the likelihood of clinical success (Drayton et al., 2020, Wu et al., 2023). Moreover, nanotechnology has addressed the deficiencies of HDPs and propelled the development of clinical antimicrobials through various nanosystem modifications (Branco et al., 2011, Yang et al., 2021).

Invading bacteria are usually trapped in phagolysosomes, where reactive oxygen species (ROS), reactive nitrogen species, and lysozymes synergistically eliminate these bacteria (Pauwels et al., 2017). Although HDPs-enhanced phagocytosis is a promising immediate response to bacterial infections, some facultative intracellular bacteria, including Mycobacterium, Salmonella, Listeria, and Brucella, have developed immune escape mechanisms to evade phagolysosomal killing, resulting in intracellular survival and recurrent infections (Brezden et al., 2016, Lewis et al., 2016). In response to this situation, the human immune system has produced a unique HDP molecule, human α‑defensin 6 (HD6). HD6 is a 32-residue cysteine-rich peptide expressed and secreted by Paneth cells. HD6 does not directly kill microbes when bound to bacterial surface proteins; however, it self-assembles into supramolecular nanonets to entrap bacteria, inhibiting bacterial invasion of host cells (Ayabe et al., 2000, Chu et al., 2012). This new antibacterial strategy of "entangle without attacking" may lead to less microbial resistance than traditional HDPs with direct microbicidal properties (Gorr et al., 2008). Moreover, human β-defensin-1 (hBD-1) has been reported to have similar bacteria-entrapping functions; thus, mimicking the HD6 host-defense strategy may provide a novel therapeutic strategy for combating microbial infections (Raschig et al., 2017).

HDPs have important roles in the body's response to microbial infection and inflammation (Andersson et al., 2016). These peptides have antibacterial, antiviral, antifungal, and host-directed immunomodulatory properties. The antimicrobial functions of HDPs have previously been reviewed extensively (Lazzaro et al., 2020, Nguyen et al., 2011). In this review, we focus on the functions that have the most biological significance in vivo, particularly the immunomodulatory and bacteria-agglutinating functions that allow them to eradicate bacterial infection. The optimization of synthetic HDPs for the aforementioned functions is described further, which may increase the chances of clinical success. We propose that in the future, anti-infective therapeutic peptides with combined bacteria-agglutinating and immunomodulatory properties should be developed as a potent way to control bacterial infection.

Furthermore, rapid degradation by blood proteases combined with quick withdrawal from circulation by kidney filtration or the reticuloendothelial system (RES) limited the number of systemically administered HDPs (Ong et al., 2014). Therefore, it is imperative to enhance the targeted delivery of HDPs and develop smart formulation strategies that can effectively overcome their chemical and metabolic instability, offering promising opportunities for their clinical translation (Drayton et al., 2021, Drayton et al., 2020). Notably, some native HDPs, such as human cathelicidin LL-37 and protegrin-1 (PG-1), can interact with the host cell membrane and the bacterial membrane through nonspecific mechanisms (Bankell et al., 2021, Soundrarajan et al., 2019). Furthermore, closely related peptides to the aforementioned have potent hemolytic, neurotoxic, or other toxic activities. This lack of specificity has raised concerns, although their properties measured on isolated cells may be inapplicable in vivo due to the complex in vivo conditions (Bell, 2011).