Since Alexander Fleming's discovery of penicillin in 1928, antibiotics have played a crucial role in saving lives and ushering in a transformative era in medicine. Nevertheless, decades of widespread antibiotic use have led to the rapid emergence and global spread of antibiotic-resistant bacteria, raising grave concerns among healthcare professionals and public health authorities about the prospect of a "post-antibiotic era" (Contractor and Arakera, 2023). A 2024 study published in The Lancet provided a comprehensive analysis of the global burden of bacterial antimicrobial resistance (AMR) from 1990 to 2021, with projections extending to 2050. In 2021, an estimated 4.71 million deaths were associated with bacterial AMR, of which 1.14 million were directly attributable to AMR. Furthermore, under a reference scenario assuming no additional interventions, projections for 2050 estimate 1.91 million annual deaths directly attributable to AMR and 8.22 million deaths associated with AMR (Naghavi et al., 2024). These health burdens are expected to be accompanied by approximately $100 trillion in cumulative economic losses linked to AMR by 2050 (Ahmed et al., 2024). Of particular concern is the growing prevalence of multidrug resistance among hospital-acquired pathogens, which poses a significant public health threat and imposes a considerable economic burden on healthcare systems globally (Freitas and Werner, 2023). On May 17, 2024, the World Health Organization (WHO) published an updated list of the most dangerous drug-resistant pathogens threatening human health. Among these, carbapenem-resistant Acinetobacter baumannii, Enterobacterales, and rifampicin-resistant Mycobacterium tuberculosis were identified as the three highest-priority pathogens. However, the pipeline for new antibiotic development remains critically limited, with only a small number of promising candidates currently in clinical trials (Willyard, 2017).

Antimicrobial peptides (AMPs) have been widely regarded as a promising strategy to combat MDR bacteria (Brogden, 2005). Unlike conventional antibiotics, which target specific receptors (Kohanski et al., 2010), AMPs interact with microbial membranes through electrostatic interactions and physically disrupt the bacterial morphology (Zasloff, 2002). Furthermore, in vitro studies have demonstrated that direct antimicrobial activity is not confined to the previously proposed mechanisms of membrane disruption and/or cell lysis but also encompasses interference with membrane-associated biosynthesis, cytoplasmic macromolecular synthesis, and metabolic functions (Gao et al., 2024a, Gao et al., 2024c, Lai et al., 2021). In addition to their direct antimicrobial activities, AMPs exhibit additional antimicrobial effects by suppressing biofilm formation and inducing the dissolution of pre-existing biofilms (Gao et al., 2024b), attracting phagocytes through chemotaxis, mediating non-opsonic phagocytosis, and regualting inflammatory response (Chung and Kocks, 2011, Gao et al., 2024a, Ma et al., 2025). The diverse antimicrobial mechanisms make AMPs less probable for bacteria to develop resistance.

Decades of research have advanced several peptide-based antimicrobial agents into clinical application, including gramicidin, daptomycin, and colistin. However, strictly speaking, these are all non-ribosomally synthesized compounds, which some academic circles refer to as "peptide antibiotics" (Awan et al., 2017). It is crucial to clarify that only ribosomally synthesized peptides should be termed AMPs. In practice, truly ribosomally synthesized AMPs are rarely seen in clinical trials, with most candidates being developed for local application. For example, LL-37 is in clinical trials for diabetic foot ulcer (Phase II, NCT04098562), Omiganan for atopic dermatitis (Phase II, NCT03091426) and seborrheic dermatitis (Phase II, NCT03688971), and PAC-113 for oral candidiasis (Phase II, NCT00659971). However, the percentage of those receiving marketing approval is significantly lower than the number of AMP-based drugs entering clinical trials. The clinical translation of AMPs faces two fundamental pharmacological barriers. First, AMPs exhibit exceptionally low oral bioavailability, primarily due to enzymatic degradation in the gastrointestinal tract and poor penetration through the intestinal mucosa (Vlieghe et al., 2010). Second, their systemic applications are significantly hindered by rapid plasma proteolysis and accelerated hepatic/renal clearance (Alves et al., 2024).

To overcome the critical barriers hindering the clinical translation of AMPs, enhancing their bioavailability and stability remains essential. This review systematically summarizes recent advances in delivery systems and structural modification strategies designed to address the limitations of AMPs. Importantly, we go beyond conventional approaches by summarizing a synergistic combination of protective delivery platforms (e.g., nanocarriers) with rational molecular design techniques (e.g., incorporation of unnatural residues, cyclization). This integrated "delivery + design" strategy aims to mitigate the inherent trade-offs commonly observed when these methods are applied separately. By introducing this comprehensive perspective, this review presents a novel and effective conceptual framework that offers researchers transformative approaches for improving AMP performance and expediting their therapeutic development.