Engineering host-defense peptides enhanced by artificial intelligence and nano delivery systems to overcome biofilms and antimicrobial resistance

Abstract

Infections caused by bacteria pose a risk to humanity as drugs become increasingly ineffective as resistance to bacterial strains emerge along with biofilm and persister formation. This review critically evaluates host defense peptides, rational design strategies that have guided next-generation antimicrobial peptide (AMP) discovery, and their current limitations. We also highlight optimization approaches including sequence engineering and chemical modification, synergistic combinations of antibiotics or adjuvants, and nanoscale delivery platforms that enhance stability, targeted delivery, and biofilm penetration. We also discuss the key chemical properties, delivery kinetics, and stimuli-responsive drug delivery for antibacterial and antibiofilm actions as well as the toxic effects of organic- and inorganic-based AMP delivery platforms. This underlines the importance of diverse modification techniques and artificial intelligence (AI)-assisted designs to improve the antibacterial activity, stability, and biocompatibility of AMPs. This study examines the latest advances in the combination of AMPs with drug delivery systems to improve clinical outcomes. Finally, the review discusses the clinical status, research gaps, current obstacles, and prospects of AMPs in antimicrobial resistance (AMR) therapy, offering key findings for the development of innovative AMPs with significant antibacterial activity, stability, and safety for AMR treatment.

Keywords

Antimicrobial peptides / Drug delivery / Bacterial infections

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

CRediT authorship contribution statement

Raman Krishnamoorthi: Writing – review & editing, Writing – original draft, Validation, Supervision, Formal analysis, Conceptualization. Muthuramalingam Kaviyadharshini: Writing – original draft, Formal analysis, Conceptualization. Pambayan Ulagan Mahalingam: Writing – review & editing, Validation, Conceptualization. Moovendran Srinivash: Writing – review & editing, Software, Data curation. Pitchaimuthu Rajkannan: Software, Formal analysis, Data curation. Mohan Keerthivsan: Writing – original draft, Software, Formal analysis. Paulraj Suganya: Writing – review & editing, Validation, Formal analysis, Data curation. Arokia Vijaya Anand Mariadoss: Writing – review & editing, Visualization, Validation.

References

[1] S.Y. Tan, Y. Tatsumura, Alexander Fleming (1881—1955): discoverer of penicillin, Singapore Med. J. 56 (2015) 366-367, doi: 10.11622/smedj.2015105.

[2] B.L. Ligon, Sir Howard Walter Florey—the force behind the development of penicillin, Semin. Pediatr. Infect. Dis. 15 (2004) 109-114, doi: 10.1053/j.spid.2004.04.001.

[3] B. Zakeri, T.K. Lu, Synthetic biology of antimicrobial discovery, ACS Synth. Biol. 2 (2013) 358-372, doi: 10.1021/sb300101g.

[4] M.J. McPhillie, R.M. Cain, S. Narramore, C.W.G. Fishwick, K.J. Simmons, Computational methods to identify new antibacterial targets, Chem. Biol. Drug Des. 85 (2015) 22-29, doi: 10.1111/cbdd.12385.

[5] M. Srinivash, R. Krishnamoorthi, P.U. Mahalingam, B. Malaikozhundan, S. Bharathakumar, K. Gurushankar, K. Dhanapal, K. Karuppa Samy, A. Babu Perumal, Nanomedicine for drug resistant pathogens and COVID—19 using mushroom nanocomposite inspired with bacteriocin — A review, Inorg. Chem. Commun. 152 (2023) 110682, doi: 10.1016/j.inoche.2023.110682.

[6] M. Galgano, F. Pellegrini, E. Catalano, L. Capozzi, L. Del Sambro, A. Sposato, M.S. Lucente, V.I. Vasinioti, C. Catella, A.E. Odigie, M. Tempesta, A. Pratelli, P. Capozza, Acquired bacterial resistance to antibiotics and resistance genes: from past to future, Antibiotics 14 (2025) 222, doi: 10.3390/antibiotics14030222.

[7] A. Krishnamoorthi, R. Hsiao, C.Y. Chou, Y.P. Mahalingam, P.U. Fang, J.Y. Alshetaili, Green synthesis of a bacitracin@Ag—CeO2 nanocomposite@hydrogel for dual antibiofilm and anti—inflammatory therapy against MRSA wound infections, J. Mater. Chem. B 14 (2026) 4125-4143, doi: 10.1039/D5TB02286J.

[8] P.r. Shankar, Book review: tackling drug—resistant infections globally, Arch. Pharm. Pract. 7 (2016) 110, doi: 10.4103/2045—080x.186181.

[9] L.C. Antochevis, C.M. Wilhelm, B. Arns, D. Sganzerla, L.O. Sudbrack, T.C.R.L. Nogueira, R.D. Guzman, A.S. Martins, D.S. Cappa, Â.C. Santos, J.C. Pascual, V.H. Perugini, E.C. Vespero, M.H.P. Rigatto, D.C. Pereira, L. Lutz, R.S. Leão, E.A. Marques, D.M. Henrique, A.A.M. Coelho, L.L. Frutuoso, E.E. de A Sousa, L.F. Abreu Guimarães, A.L.P. Ferreira, A.C. Castiñeiras, M.D. Alves, J.P. Telles, C.H. Yamada, F.P. de Almeida, E.S. Girão, P.C.P. de Sousa, A.G.N.D. de Melo, E.T. Mendes, V. de F.D. Rocha, E. da S. Neves, M.T. Ribeiro, C.E.F. Starling, M.S. Oliveira, J.L.M. Sampaio, A.F. Martins, A.L. Barth, A.P. Zavascki, World Health Organization priority antimicrobial resistance in Enterobacterales, Acinetobacter baumannii, Pseudomonas aeruginosa, Staphylococcus aureus and Enterococcus faecium healthcare—associated bloodstream infections in Brazil (ASCENSION): a prospect, Lancet Reg. Heal. — Am. 43 (2025) 101004, doi: 10.1016/j.lana.2025.101004.

[10] D. Sharma, L. Misba, A.U. Khan, Antimicrob. Resist. Infect. Control., Antimicrob. Resist. Infect. Control 8 (2019) 1-10.

[11] J. Gruszecka, R. Filip, Bacterial biofilms —A threat to biliary stents, understanding their formation, Clin. Conseq. Manag., Med 61 (2025) 512, doi: 10.3390/medicina61030512.

[12] M.I. Hasan, S. Aggarwal, Matrix matters: how extracellular substances shape biofilm structure and mechanical properties, Colloids Surf. B Biointerfaces 246 (2025) 114341, doi: 10.1016/j.colsurfb.2024.114341.

[13] J.E. Sulaiman, H. Lam, Evolution of bacterial tolerance under antibiotic treatment and its implications on the development of resistance, Front. Microbiol. 12 (2021) 1-9, doi: 10.3389/fmicb.2021.617412.

[14] K. Gerdes, S. Semsey, Pumping persisters, Nature 534 (2016) 41-42, doi: 10.1038/nature18442.

[15] N.F. Kamaruzzaman, S. Kendall, L. Good, Targeting the hard to reach: challenges and novel strategies in the treatment of intracellular bacterial infections, Br. J. Pharmacol. 174 (2017) 2225-2236, doi: 10.1111/bph.13664.

[16] M. Yoshida, T. Hinkley, S. Tsuda, Y.M. Abul—Haija, R.T. McBurney, V. Kulikov, J.S. Mathieson, S. Galiñanes Reyes, M.D. Castro, L. Cronin, Using evolutionary algorithms and machine learning to explore sequence space for the discovery of antimicrobial peptides, Chem 4 (2018) 533-543, doi: 10.1016/j.chempr.2018.01.005.

[17] C. Sahli, S.E. Moya, J.S. Lomas, C. Gravier—Pelletier, R. Briandet, M. Hémadi, Recent advances in nanotechnology for eradicating bacterial biofilm, Theranostics 12 (2022) 2383-2405, doi: 10.7150/thno.67296.

[18] V. Somase, S.A. Desai, V.P. Patel, V. Patil, K. Bhosale, Antimicrobial peptides: potential alternative to antibiotics and overcoming limitations for future therapeutic applications, Int. J. Pept. Res. Ther. 30 (2024) 1-29, doi: 10.1007/s10989—024—10623—9.

[19] M. Alzain, H. Daghistani, T. Shamrani, Y. Almoghrabi, Y. Daghistani, O.S. Alharbi, A.M. Sait, M. Mufrrih, W. Alhazmi, M.A. Alqarni, B.H. Saleh, M.A. Zubair, N.A. Juma, H.A. Niyazi, H.A. Niyazi, W.S. Halabi, R. Altalhi, I. Kazmi, H.N. Altayb, K. Ibrahem, A. Alfadil, Antimicrobial peptides: mechanisms, applications, and therapeutic potential, Infect. Drug Resist. 18 (2025) 4385-4426, doi: 10.2147/IDR.S514825.

[20] R. Krishnamoorthi, M. Srinivash, P. Ulagan, B. Malaikozhundan, P. Suganya, K. Gurushankar, International Journal of biological macromolecules antimicrobial, antibiofilm, antioxidant and cytotoxic effects of bacteriocin by lactococcus lactis strain CH3 isolated from fermented dairy products — an in vitro and in silico approach , Int. J. Biol. Macromol. 220 (2022) 291-306, doi: 10.1016/j.ijbiomac.2022.08.087.

[21] M. Srinivash, R. Krishnamoorthi, P. Ulagan, B. Malaikozhundan, M. Kaviyadharshini, Antimicrobial, antioxidant and anticancer properties of bioactive bacteriocins produced by lactococcus hircilactis CH4 and Lactobacillus delbrueckii GRIPUMSK isolated from homemade fermented dairy products, Int. Dairy J. 171 (2025) 106395, doi: 10.1016/j.idairyj.2025.106395.

[22] Y. Huan, Q. Kong, H. Mou, H. Yi, Antimicrobial peptides: classification, design, application and research progress in multiple fields, Front. Microbiol. 11 (2020) 1-21, doi: 10.3389/fmicb.2020.582779.

[23] V. Kumaresan, Y. Kamaraj, S. Subramaniyan, G. Punamalai, Understanding the Dynamics of Human Defensin Antimicrobial Peptides: Pathogen Resistance and Commensal Induction, Springer US, 2024, doi: 10.1007/s12010—024—04893—8.

[24] P. Gagat, M. Ostrówka, A. Duda—Madej, P. Mackiewicz, Enhancing antimicrobial peptide activity through modifications of charge, hydrophobicity, and structure, Int. J. Mol. Sci. 25 (2024) 10821, doi: 10.3390/ijms251910821.

[25] L.T. Nguyen, E.F. Haney, H.J. Vogel, The expanding scope of antimicrobial peptide structures and their modes of action, Trends Biotechnol. 29 (2011) 464-472, doi: 10.1016/j.tibtech.2011.05.001.

[26] S. He, C.M. Deber, Interaction of designed cationic antimicrobial peptides with the outer membrane of gram—negative bacteria, Sci. Rep. 14 (2024) 1-12, doi: 10.1038/s41598—024—51716—1.

[27] M. Neghabi Hajigha, B. Hajikhani, M. Vaezjalali, H. Samadi Kafil, R. Kazemzadeh Anari, M. Goudarzi, Antiviral and antibacterial peptides: mechanisms of action, Heliyon 10 (2024) e40121, doi: 10.1016/j.heliyon.2024.e40121.

[28] A. Yarahmadi, H. Najafian, M.H. Yousefi, E. Khosravi, E. Shabani, H. Afkhami, S.S. Aghaei, Beyond antibiotics: exploring multifaceted approaches to combat bacterial resistance in the modern era: a comprehensive review, Front. Cell. Infect. Microbiol. 15 (2025) 1-28, doi: 10.3389/fcimb.2025.1493915.

[29] N. Mookherjee, M.A. Anderson, H.P. Haagsman, D.J. Davidson, Antimicrobial host defence peptides: functions and clinical potential, Nat. Rev. Drug Discov. 19 (2020) 311-332, doi: 10.1038/s41573—019—0058—8.

[30] A.L. Hilchie, K. Wuerth, R.E.W. Hancock, Immune modulation by multifaceted cationic host defense (antimicrobial) peptides, Nat. Chem. Biol. 9 (2013) 761-768, doi: 10.1038/nchembio.1393.

[31] M.L. Mangoni, A.M. Mcdermott, M. Zasloff, Antimicrobial peptides and wound healing: biological and therapeutic considerations, Exp. Dermatol. 25 (2016) 167-173, doi: 10.1111/exd.12929.

[32] S. Nasseri, M. Sharifi, Therapeutic potential of antimicrobial peptides for wound healing, Int. J. Pept. Res. Ther. 28 (2022) 1-15, doi: 10.1007/s10989—021—10350—5.

[33] M.H. Cardoso, R.Q. Orozco, S.B. Rezende, G. Rodrigues, K.G.N. Oshiro, E.S. Cândido, O.L. Franco, Computer—aided design of antimicrobial peptides: are we generating effective drug candidates? Front. Microbiol. 10 (2020) 1-15, doi: 10.3389/fmicb.2019.03097.

[34] H. Memariani, M. Memariani, Antibiofilm properties of cathelicidin LL—37: an in—depth review, World J. Microbiol. Biotechnol. 39 (2023), doi: 10.1007/s11274—023—03545—z.

[35] M.L. Leite, H.M. Duque, G.R. Rodrigues, N.B. da Cunha, O.L. Franco, The LL—37 domain: a clue to cathelicidin immunomodulatory response? Peptides 165 (2023) 171011, doi: 10.1016/j.peptides.2023.171011.

[36] D.S. Alexandre—Ramos, A.É. Silva—Carvalho, M.G. Lacerda, T.R.T. Serejo, O.L. Franco, R.W. Pereira, J.L. Carvalho, F.A.R. Neves, F. Saldanha—Araujo, LL—37 treatment on human peripheral blood mononuclear cells modulates immune response and promotes regulatory T—cells generation, Biomed. Pharmacother. 108 (2018) 1584-1590, doi: 10.1016/j.biopha.2018.10.014.

[37] M.J. Nell, G.S. Tjabringa, A.R. Wafelman, R. Verrijk, P.S. Hiemstra, J.W. Drijfhout, J.J. Grote, Development of novel LL—37 derived antimicrobial peptides with LPS and LTA neutralizing and antimicrobial activities for therapeutic application, Peptides 27 (2006) 649-660, doi: 10.1016/j.peptides.2005.09.016.

[38] A. De Breij, M. Riool, P.H.S. Kwakman, L. De Boer, R.A. Cordfunke, J.W. Drijfhout, O. Cohen, N. Emanuel, S.A.J. Zaat, P.H. Nibbering, T.F. Moriarty, Prevention of Staphylococcus aureus biomaterial—associated infections using a polymer—lipid coating containing the antimicrobial peptide OP—145, J. Control. Rel. 222 (2016) 1-8, doi: 10.1016/j.jconrel.2015.12.003.

[39] E.M. Haisma, A. Göblyös, B. Ravensbergen, A.E. Adriaans, R.A. Cordfunke, J. Schrumpf, R.W.A.L. Limpens, K.J.M. Schimmel, J. Den Hartigh, P.S. Hiemstra, J.W. Drijfhout, A. El Ghalbzouri, P.H. Nibbering, Antimicrobial peptide P60.4Ac—containing creams and gel for eradication of methicillin—resistant Staphylococcus aureus from cultured skin and airway epithelial surfaces, Antimicrob. Agents Chemother. 60 (2016) 4063-4072, doi: 10.1128/AAC.03001—15.

[40] N.F.A.W. Peek, M.J. Nell, R. Brand, T. Jansen—Werkhoven, E.J. Van Hoogdalem, R. Verrijk, M.J. Vonk, A.R. Wafelman, A.R.P.M. Valentijn, J.H.M. Frijns, P.S. Hiemstra, J.W. Drijfhout, P.H. Nibbering, J.J. Grote, Ototopical drops containing a novel antibacterial synthetic peptide: safety and efficacy in adults with chronic suppurative otitis media, PLoS One 15 (2020) e0231573, doi: 10.1371/journal.pone.0231573.

[41] A. De Breij, M. Riool, R.A. Cordfunke, N. Malanovic, L. De Boer, R.I. Koning, E. Ravensbergen, M. Franken, T. Van Der Heijde, B.K. Boekema, P.H.S. Kwakman, N. Kamp, A. El Ghalbzouri, K. Lohner, S.A.J. Zaat, J.W. Drijfhout, P.H. Nibbering, The antimicrobial peptide SAAP—148 combats drug—resistant bacteria and biofilms, Sci. Transl. Med. 10 (2018) 1-15, doi: 10.1126/scitranslmed.aan4044.

[42] H. Scheper, J.M. Wubbolts, J.A.M. Verhagen, A.W. de Visser, R.J.P. van der Wal, L.G. Visser, M.G.J. de Boer, P.H. Nibbering, SAAP—148 eradicates MRSA persisters within mature biofilm models simulating prosthetic joint infection, Front. Microbiol. 12 (2021) 1-10, doi: 10.3389/fmicb.2021.625952.

[43] P. Piller, H. Wolinski, R.A. Cordfunke, J.W. Drijfhout, S. Keller, K. Lohner, N. Malanovic, Membrane activity of LL—37 derived antimicrobial peptides against Enterococcus hirae: superiority of SAAP—148 over OP—145, Biomolecules 12 (2022) 523, doi: 10.3390/biom12040523.

[44] C.H. Chen, T.K. Lu, Development and challenges of antimicrobial peptides for therapeutic applications, Antibiotics 9 (2020) 24, doi: 10.3390/antibiotics9010024.

[45] G.S. Dijksteel, M.M.W. Ulrich, E. Middelkoop, B.K.H.L. Boekema, Review: lessons learned from clinical trials using antimicrobial peptides (AMPs), Front. Microbiol. 12 (2021), doi: 10.3389/fmicb.2021.616979.

[46] M. Bacalum, M. Radu, Cationic antimicrobial peptides cytotoxicity on mammalian cells: an analysis using therapeutic index integrative concept, Int. J. Pept. Res. Ther. 21 (2015) 47-55, doi: 10.1007/s10989—014—9430—z.

[47] A. Barreto—Santamaría, M.E. Patarroyo, H. Curtidor, Designing and optimizing new antimicrobial peptides: all targets are not the same, Crit. Rev. Clin. Lab. Sci. 56 (2019) 351-373, doi: 10.1080/10408363.2019.1631249.

[48] G. Laverty, Cationic antimicrobial peptide cytotoxicity, SOJ Microbiol. Infect. Dis. 2 (2014) 2-10, doi: 10.15226/sojmid.2013.00112.

[49] P. Vlieghe, V. Lisowski, J. Martinez, M. Khrestchatisky, Synthetic therapeutic peptides: science and market, Drug Discov. Today 15 (2010) 40-56, doi: 10.1016/j.drudis.2009.10.009.

[50] A. Sivertsen, J. Isaksson, H.K.S. Leiros, J. Svenson, J.S. Svendsen, B.O. Brandsdal, Synthetic cationic antimicrobial peptides bind with their hydrophobic parts to drug site II of human serum albumin, BMC Struct. Biol. 14 (2014), doi: 10.1186/1472—6807—14—4.

[51] M. Yasir, M.D.P. Willcox, D. Dutta, Action of antimicrobial peptides against bacterial biofilms, Materials 11 (2018) 2468, doi: 10.3390/ma11122468.

[52] G.S. Dijksteel, M.M.W. Ulrich, M. Vlig, P.H. Nibbering, R.A. Cordfunke, J.W. Drijfhout, E. Middelkoop, B.K.H.L. Boekema, Potential factors contributing to the poor antimicrobial efficacy of SAAP—148 in a rat wound infection model, Ann. Clin. Microbiol. Antimicrob. 18 (2019) 1-12, doi: 10.1186/s12941—019—0336—7.

[53] G.S. Dijksteel, M.M.W. Ulrich, P.H. Nibbering, R.A. Cordfunke, J.W. Drijfhout, E. Middelkoop, B.K.H.L. Boekema, The functional stability, bioactivity and safety profile of synthetic antimicrobial peptide SAAP—148, J. Microbiol. Antimicrob. 12 (2020) 70-80, doi: 10.5897/JMA2020.0437.

[54] R. Bellavita, S. Braccia, S. Galdiero, A. Falanga, Glycosylation and lipidation strategies: approaches for improving antimicrobial peptide efficacy, Pharmaceuticals 16 (2023) 439, doi: 10.3390/ph16030439.

[55] T.T.L. Nguyen, A. Edelen, B. Neighbors, D.A. Sabatini, Biocompatible lecithin—based microemulsions with rhamnolipid and sophorolipid biosurfactants: formulation and potential applications, J. Colloid Interface Sci. 348 (2010) 498-504, doi: 10.1016/j.jcis.2010.04.053.

[56] Y. Zhao, M. Zhang, S. Qiu, J. Wang, J. Peng, P. Zhao, R. Zhu, H. Wang, Y. Li, K. Wang, W. Yan, R. Wang, Antimicrobial activity and stability of the D—amino acid substituted derivatives of antimicrobial peptide polybia—MPI, AMB Express 6 (2016), doi: 10.1186/s13568—016—0295—8.

[57] S.P. Chen, E.H.L. Chen, S.Y. Yang, P.S. Kuo, H.M. Jan, T.C. Yang, M.Y. Hsieh, K.T. Lee, C.H. Lin, R.P.Y. Chen, A systematic study of the stability, safety, and efficacy of the de novo designed antimicrobial peptide PepD2 and its modified derivatives against Acinetobacter baumannii, Front. Microbiol. 12 (2021) 1-12, doi: 10.3389/fmicb.2021.678330.

[58] J. Kindrachuk, E. Scruten, S. Attah—Poku, K. Bell, A. Potter, L.A. Babiuk, P.J. Griebel, S. Napper, Stability, toxicity, and biological activity of host defense peptide BMAP28 and its inversed and retro—inversed isomers, Biopolymers 96 (2011) 14-24, doi: 10.1002/bip.21441.

[59] S. Ramesh, T. Govender, H.G. Kruger, B.G. de la Torre, F. Albericio, Short AntiMicrobial peptides (SAMPs) as a class of extraordinary promising therapeutic agents, J. Pept. Sci. 22 (2016) 438-451, doi: 10.1002/psc.2894.

[60] N. Kaur, R. Dilawari, A. Kaur, G. Sahni, P. Rishi, Recombinant expression, purification and PEGylation of Paneth cell peptide (cryptdin—2) with value added attributes against Staphylococcus aureus, Sci. Rep. 10 (2020) 1-14, doi: 10.1038/s41598—020—69039—2.

[61] S. Singh, P. Papareddy, M. Mörgelin, A. Schmidtchen, M. Malmsten, Effects of PEGylation on membrane and lipopolysaccharide interactions of host defense peptides, Biomacromolecules 15 (2014) 1337-1345, doi: 10.1021/bm401884e.

[62] R. Manteghi, E. Pallagi, G. Olajos, I. Csóka, Pegylation and formulation strategy of anti—microbial peptide (AMP) according to the quality by design approach, Eur. J. Pharm. Sci. 144 (2020) 105197, doi: 10.1016/j.ejps.2019.105197.

[63] Q. Cui, Q. jun Xu, L. Liu, L. li Guan, X. yun Jiang, M. Inam, L. cong Kong, H.X. Ma, Preparation, characterization and pharmacokinetic study of N—terminal PEGylated D—form antimicrobial peptide OM19r—8, J. Pharm. Sci. 110 (2021) 1111-1119, doi: 10.1016/j.xphs.2020.10.048.

[64] C.J. Morris, K. Beck, M.A. Fox, D. Ulaeto, G.C. Clark, M. Gumbleton, Pegylation of antimicrobial peptides maintains the active peptide conformation, model membrane interactions, and antimicrobial activity while improving lung tissue biocompatibility following airway delivery, Antimicrob. Agents Chemother. 56 (2012) 3298-3308, doi: 10.1128/AAC.06335—11.

[65] G. Guidotti, L. Brambilla, D. Rossi, Cell—penetrating peptides: from basic research to clinics, Trends Pharmacol. Sci. 38 (2017) 406-424, doi: 10.1016/j.tips.2017.01.003.

[66] S.M. Zeiders, J. Chmielewski, Antibiotic—cell—penetrating peptide conjugates targeting challenging drug—resistant and intracellular pathogenic bacteria, Chem. Biol. Drug Des. 98 (2021) 762-778, doi: 10.1111/cbdd.13930.

[67] F. Milletti, Cell—penetrating peptides: classes, origin, and current landscape, Drug Discov. Today 17 (2012) 850-860, doi: 10.1016/j.drudis.2012.03.002.

[68] D. Derossi, A.H. Joliot, G. Chassaing, A. Prochiantz, The third helix of the Antennapedia homeodomain translocates through biological membranes, J. Biol. Chem. 269 (1994) 10444-10450, doi: 10.1016/s0021—9258(17)34080—2.

[69] J. Park, J. Ryu, K.A. Kim, H.J. Lee, J.H. Bahn, K. Han, E.Y. Choi, K.S. Lee, H.Y. Kwon, S.Y. Choi, Mutational analysis of a human immunodeficiency virus type 1 tat protein transduction domain which is required for delivery of an exogenous protein into mammalian cells, J. Gen. Virol. 83 (2002) 1173-1181, doi: 10.1099/0022—1317—83—5—1173.

[70] C.Y. Jiao, D. Delaroche, F. Burlina, I.D. Alves, G. Chassaing, S. Sagan, Translocation and endocytosis for cell—penetrating peptide internalization, J. Biol. Chem. 284 (2009) 33957-33965, doi: 10.1074/jbc.M109.056309.

[71] A. Bocsik, I. Gróf, L. Kiss, F. Ötvös, O. Zsíros, L. Daruka, L. Fülöp, M. Vastag, Á. Kittel, N. Imre, T.A. Martinek, C. Pál, P. Szabó—Révész, M.A. Deli, Dual action of the PN159/KLAL/MAP peptide: increase of drug penetration across caco—2 intestinal barrier model by modulation of tight junctions and plasma membrane permeability, Pharmaceutics 11 (2019) 73, doi: 10.3390/pharmaceutics11020073.

[72] C. Li, T. Li, X. Tian, W. An, Z. Wang, B. Han, H. Tao, J. Wang, X. Wang, Research progress on the PEGylation of therapeutic proteins and peptides (TPPs), Front. Pharmacol. 15 (2024) 1-17, doi: 10.3389/fphar.2024.1353626.

[73] T. Rounds, S.K. Straus, Lipidation of antimicrobial peptides as a design strategy for future alternatives to antibiotics, Int. J. Mol. Sci. 21 (2020) 9692, doi: 10.3390/ijms21249692.

[74] T. Schneider, A. Müller, H. Miess, H. Gross, Cyclic lipopeptides as antibacterial agents — potent antibiotic activity mediated by intriguing mode of actions, Int. J. Med. Microbiol. 304 (2014) 37-43, doi: 10.1016/j.ijmm.2013.08.009.

[75] S.P. Selvaraj, J.Y. Chen, Conjugation of antimicrobial peptides to enhance therapeutic efficacy, Eur. J. Med. Chem. 259 (2023) 115680, doi: 10.1016/j.ejmech.2023.115680.

[76] C.D. Doern, When does 2 plus 2 equal 5? A review of antimicrobial synergy testing, J. Clin. Microbiol. 52 (2014) 4124-4128, doi: 10.1128/JCM.01121—14.

[77] A. Lewies, L.H. Du Plessis, J.F. Wentzel, Antimicrobial peptides: the Achilles’ Heel of antibiotic resistance? Probiotics Antimicrob. Proteins 11 (2019) 370-381, doi: 10.1007/s12602—018—9465—0.

[78] X. Xu, L. Xu, G. Yuan, Y. Wang, Y. Qu, M. Zhou, Synergistic combination of two antimicrobial agents closing each other’s mutant selection windows to prevent antimicrobial resistance, Sci. Rep. 8 (2018) 1-7, doi: 10.1038/s41598—018—25714—z.

[79] G. Yu, D.Y. Baeder, R.R. Regoes, J. Rolff, Combination effects of antimicrobial peptides, Antimicrob. Agents Chemother. 60 (2016) 1717-1724, doi: 10.1128/AAC.02434—15.

[80] S. Dhanam, T. Arumugam, A.M. Elgorban, N. Rameshkumar, M. Krishnan, M. Govarthanan, N. Kayalvizhi, Enhanced anti—methicillin—resistant Staphylococcus aureus activity of bacteriocin by encapsulation on silver nanoparticles, Appl. Nanosci. 13 (2023) 1301-1312, doi: 10.1007/s13204—021—02023—y.

[81] L.R. Pizzolato—Cezar, N.M. Okuda—Shinagawa, M.T. Machini, Combinatory therapy antimicrobial peptide—antibiotic to minimize the ongoing rise of resistance, Front. Microbiol. 10 (2019) 1-5, doi: 10.3389/fmicb.2019.01703.

[82] L. Grassi, G. Maisetta, S. Esin, G. Batoni, Combination strategies to enhance the efficacy of antimicrobial peptides against bacterial biofilms, Front. Microbiol. 8 (2017) 1-8, doi: 10.3389/fmicb.2017.02409.

[83] S.M. Ribeiro, C. De La Fuente—Núñez, B. Baquir, C. Faria—Junior, O.L. Franco, R.E.W. Hancock, Antibiofilm peptides increase the susceptibility of carbapenemase—producing Klebsiella pneumoniae clinical isolates to β—lactam antibiotics , Antimicrob. Agents Chemother. 59 (2015) 3906-3912, doi: 10.1128/AAC.00092—15.

[84] B.C. Koppen, P.P.G. Mulder, L. de Boer, M. Riool, J.W. Drijfhout, S.A.J. Zaat, Synergistic microbicidal effect of cationic antimicrobial peptides and teicoplanin against planktonic and biofilm—encased Staphylococcus aureus, Int. J. Antimicrob. Agents 53 (2019) 143-151, doi: 10.1016/j.ijantimicag.2018.10.002.

[85] S. Li, P. She, L. Zhou, X. Zeng, L. Xu, Y. Liu, L. Chen, Y. Wu, High—throughput identification of antibacterials against Pseudomonas aeruginosa, Front. Microbiol. 11 (2020) 1-12, doi: 10.3389/fmicb.2020.591426.

[86] T. Ludwig, R. Hoffmann, A. Krizsan, Construction and characterization of T7 bacteriophages harboring apidaecin—derived sequences, Curr. Issues Mol. Biol. 44 (2022) 2554-2568, doi: 10.3390/CIMB44060174.

[87] A. Gouveia, D. Pinto, H. Veiga, W. Antunes, M.G. Pinho, C. São—José, Synthetic antimicrobial peptides as enhancers of the bacteriolytic action of staphylococcal phage endolysins, Sci. Rep. 12 (2022) 1-16, doi: 10.1038/s41598—022—05361—1.

[88] T. Doolin, H.M. Amir, L. Duong, R. Rosenzweig, L.A. Urban, M. Bosch, A. Pol, S.P. Gross, A. Siryaporn, Mammalian histones facilitate antimicrobial synergy by disrupting the bacterial proton gradient and chromosome organization, Nat. Commun. 11 (2020) 1-16, doi: 10.1038/s41467—020—17699—z.

[89] S. Ruden, K. Hilpert, M. Berditsch, P. Wadhwani, A.S. Ulrich, Synergistic interaction between silver nanoparticles and membrane—permeabilizing antimicrobial peptides, Antimicrob. Agents Chemother. 53 (2009) 3538-3540, doi: 10.1128/AAC.01106—08.

[90] O. Cirioni, F. Mocchegiani, I. Cacciatore, J. Vecchiet, C. Silvestri, L. Baldassarre, C. Ucciferri, E. Orsetti, P. Castelli, M. Provinciali, M. Vivarelli, E. Fornasari, A. Giacometti, Quorum sensing inhibitor FS3—coated vascular graft enhances daptomycin efficacy in a rat model of staphylococcal infection, Peptides 40 (2013) 77-81, doi: 10.1016/j.peptides.2012.12.002.

[91] P.V. Gawande, K.P. Leung, S. Madhyastha, Antibiofilm and antimicrobial efficacy of Dispersinb®—KSL—w peptide—based wound gel against chronic wound infection associated bacteria, Curr. Microbiol. 68 (2014) 635-641, doi: 10.1007/s00284—014—0519—6.

[92] G. Maisetta, L. Grassi, M. Di Luca, S. Bombardelli, C. Medici, F.L. Brancatisano, S. Esin, G. Batoni, Anti—biofilm properties of the antimicrobial peptide temporin 1Tb and its ability, in combination with EDTA, to eradicate Staphylococcus epidermidis biofilms on silicone catheters, Biofouling 32 (2016) 787-800, doi: 10.1080/08927014.2016.1194401.

[93] L. Grassi, G. Maisetta, G. Maccari, S. Esin, G. Batoni, Analogs of the frog—skin antimicrobial peptide temporin 1Tb exhibit a wider spectrum of activity and a stronger antibiofilm potential as compared to the parental peptide, Front. Chem. 5 (2017) 1-13, doi: 10.3389/fchem.2017.00024.

[94] G. Maisetta, L. Grassi, S. Esin, I. Serra, M.A. Scorciapino, A.C. Rinaldi, G. Batoni, The semi—synthetic peptide Lin—SB056—1 in combination with EDTA exerts strong antimicrobial and antibiofilm activity against pseudomonas aeruginosa in conditions mimicking cystic fibrosis sputum, Int. J. Mol. Sci. 18 (2017) 1994, doi: 10.3390/ijms18091994.

[95] P.M.S.D. Cal, M.J. Matos, G.J.L. Bernardes, Trends in therapeutic drug conjugates for bacterial diseases: a patent review, Expert Opin. Ther. Pat. 27 (2017) 179-189, doi: 10.1080/13543776.2017.1259411.

[96] K. Park, Controlled drug delivery systems: past forward and future back, J. Control. Rel. 190 (2014) 3-8, doi: 10.1016/j.jconrel.2014.03.054.

[97] G. Unnikrishnan, A. Joy, M. Megha, E. Kolanthai, M. Senthilkumar, Exploration of Inorganic Nanoparticles for Revolutionary Drug Delivery Applications: a Critical Review, Springer US, 2023, doi: 10.1186/s11671—023—03943—0.

[98] J. Jampilek, K. Kralova, Advances in nanostructures for antimicrobial therapy, Materials (2022) 2388, doi: 10.3390/ma15072388.

[99] C.A. Roque—Borda, P. Bento da Silva, M.C. Rodrigues, L.D. Di Filippo, J.L. Duarte, M. Chorilli, E.F. Vicente, S.S. Garrido, F. Rogério Pavan, Pharmaceutical nanotechnology: antimicrobial peptides as potential new drugs against WHO list of critical, high, and medium priority bacteria, Eur. J. Med. Chem. 241 (2022) 114640, doi: 10.1016/j.ejmech.2022.114640.

[100] E. Imperlini, F. Massaro, F. Buonocore, Antimicrobial peptides against bacterial pathogens: innovative delivery nanosystems for pharmaceutical applications, Antibiotics 12 (2023) 184, doi: 10.3390/antibiotics12010184.

[101] M.T. Campos, L.S. Pires, F.D. Magalhães, M.J. Oliveira, A.M. Pinto, Self—assembled inorganic nanomaterials for biomedical applications, Nanoscale 17 (2025) 5526-5570, doi: 10.1039/d4nr04537h.

[102] B.H. Alshammari, M.M.A. Lashin, M.A. Mahmood, F.S. Al—Mubaddel, N. Ilyas, N. Rahman, M. Sohail, A. Khan, S.S. Abdullaev, R. Khan, Organic and inorganic nanomaterials: fabrication, properties and applications, RSC Adv. 13 (2023) 13735-13785, doi: 10.1039/d3ra01421e.

[103] A.M. Carmona—Ribeiro, P.M. Araújo, Antimicrobial polymer−based assemblies: a review, Int. J. Mol. Sci. 22 (2021) 5424, doi: 10.3390/ijms22115424.

[104] R.K. Thapa, D.B. Diep, H.H. Tønnesen, Nanomedicine—based antimicrobial peptide delivery for bacterial infections: recent advances and future prospects, J. Pharm. Investig. 51 (2021) 377-398, doi: 10.1007/s40005—021—00525—z.

[105] M.R. Ki, S.H. Kim, T.I. Park, S.P. Pack, Self—entrapment of antimicrobial peptides in silica particles for stable and effective antimicrobial peptide delivery system, Int. J. Mol. Sci. 24 (2023) 16423, doi: 10.3390/ijms242216423.

[106] S. Ron—Doitch, B. Sawodny, A. Kühbacher, M.M.N. David, A. Samanta, J. Phopase, A. Burger—Kentischer, M. Griffith, G. Golomb, S. Rupp, Reduced cytotoxicity and enhanced bioactivity of cationic antimicrobial peptides liposomes in cell cultures and 3D epidermis model against HSV, J. Control. Rel. 229 (2016) 163-171, doi: 10.1016/j.jconrel.2016.03.025.

[107] S. Menina, J. Eisenbeis, M.A.M. Kamal, M. Koch, M. Bischoff, S. Gordon, B. Loretz, C.M. Lehr, Bioinspired liposomes for oral delivery of Colistin to combat intracellular infections by Salmonella enterica, Adv. Healthc. Mater. 8 (2019), doi: 10.1002/adhm.201900564.

[108] M. Faya, H.A. Hazzah, C.A. Omolo, N. Agrawal, R. Maji, P. Walvekar, C. Mocktar, B. Nkambule, S. Rambharose, F. Albericio, B.G. de la Torre, T. Govender, Novel formulation of antimicrobial peptides enhances antimicrobial activity against methicillin—resistant Staphylococcus aureus (MRSA), Amino Acids 52 (2020) 1439-1457, doi: 10.1007/s00726—020—02903—7.

[109] N. Hoshyar, S. Gray, H. Han, G. Bao, The effect of nanoparticle size on in vivo pharmacokinetics and cellular interaction , Nanomedicine 11 (2016) 673-692, doi: 10.2217/nnm.16.5.

[110] M. González—Alvarez, I. González—Alvarez, M. Bermejo, Hydrogels: an interesting strategy for smart drug delivery, Ther. Deliv. 4 (2013) 157-160, doi: 10.4155/tde.12.142.

[111] S.N. Klodzińska, T.V.F. Esposito, M. Agnoletti, C. Rodríguez—Rodríguez, C. Blackadar, L. Wu, A. Thakur, J. Nahrstedt, T. Rades, K. Saatchi, U.O. Häfeli, H.M.ø Nielsen, Nanogel encapsulation improves pharmacokinetics and biodistribution of antimicrobial peptide LL37 upon lung deposition: in vivo evaluation by SPECT/CT , J. Control. Rel. 383 (2025) 113817, doi: 10.1016/j.jconrel.2025.113817.

[112] M.E. van Gent, T. van Baaren, S.N. Klodzińska, M. Ali, N. Dolezal, B.R. van Doodevaard, E. Bos, A.M. de Waal, R.I. Koning, J.W. Drijfhout, H.M. Nielsen, P.H. Nibbering, Encapsulation of SAAP—148 in octenyl succinic anhydride—modified hyaluronic acid nanogels for treatment of skin wound infections, Pharmaceutics 15 (2023) 429, doi: 10.3390/pharmaceutics15020429.

[113] N. Aminu, D. Alfred—Ugbenbo, O. Moradeke, M. Audu Mumuni, N. Muhammad Umar, N. Tanko, V. Raghavulu Bitra, F. Tshepo Moshapa, T. Monkgogi, C. Siok—Yee, Nanogel drug delivery system loaded with Azadirachta indica A. Juss. (Neem) For potential treatment of wound infection: development and characterization, Beni—Suef Univ, J. Basic Appl. Sci. 14 (2025), doi: 10.1186/s43088—025—00655—5.

[114] H.L. Haller, F. Sander, D. Popp, M. Rapp, B. Hartmann, M. Demircan, S.P. Nischwitz, L.P. Kamolz, Oxygen, ph, lactate, and metabolism —How old knowledge and new insights might be combined for new wound treatment, Medicine 57 (2021) 1190, doi: 10.3390/medicina57111190.

[115] M.C. Teixeira, C. Carbone, M.C. Sousa, M. Espina, M.L. Garcia, E. Sanchez—Lopez, E.B. Souto, Nanomedicines for the delivery of antimicrobial peptides (Amps), Nanomaterials 10 (2020) 560, doi: 10.3390/nano10030560.

[116] E. Beltrán—Gracia, A. López—Camacho, I. Higuera—Ciapara, J.B. Velázquez—Fernández, A.A. Vallejo—Cardona, Nanomedicine review: Clinical developments in Liposomal Applications, Springer, Vienna, 2019, doi: 10.1186/s12645—019—0055—y.

[117] T.O.B. Olusanya, R.R.H. Ahmad, D.M. Ibegbu, J.R. Smith, A.A. Elkordy, Liposomal drug delivery systems and anticancer drugs, Molecules 23 (2018) 907, doi: 10.3390/molecules23040907.

[118] A. Falanga, V. Del Genio, S. Galdiero, Peptides and dendrimers: how to combat viral and bacterial infections, Pharmaceutics 13 (2021) 101, doi: 10.3390/pharmaceutics13010101.

[119] Z. Tang, Q. Ma, X. Chen, T. Chen, Y. Ying, X. Xi, L. Wang, C. Ma, C. Shaw, M. Zhou, Recent advances and challenges in nanodelivery systems for antimicrobial peptides (AMPs), Antibiotics 10 (2021) 990, doi: 10.3390/antibiotics10080990.

[120] L. Kumar, M. Bisen, K. Harjai, S. Chhibber, S. Azizov, H. Lalhlenmawia, D. Kumar, Advances in nanotechnology for biofilm inhibition, ACS Omega 8 (2023) 21391-21409, doi: 10.1021/acsomega.3c02239.

[121] F. Bach, A.A.F. Zielinski, C.V. Helm, G.M. Maciel, A.C. Pedro, A.P. Stafussa, S. Ávila, C.W.I. Haminiuk, Bio compounds of edible mushrooms: in vitro antioxidant and antimicrobial activities , LWT 107 (2019) 214-220, doi: 10.1016/j.lwt.2019.03.017.

[122] S. Wang, C. Yan, X. Zhang, D. Shi, L. Chi, G. Luo, J. Deng, Antimicrobial peptide modification enhances the gene delivery and bactericidal efficiency of gold nanoparticles for accelerating diabetic wound healing, Biomater. Sci. 6 (2018) 2757-2772, doi: 10.1039/c8bm00807h.

[123] M. Chai, Y. Gao, J. Liu, Y. Deng, D. Hu, Q. Jin, J. Ji, Polymyxin B—polysaccharide polyion nanocomplex with improved biocompatibility and unaffected antibacterial activity for acute lung infection management, Adv. Healthc. Mater. 9 (2020) 1-8, doi: 10.1002/adhm.201901542.

[124] Z. Ye, H. Zhu, S. Zhang, J. Li, J. Wang, E. Wang, Highly efficient nanomedicine from cationic antimicrobial peptide—protected Ag nanoclusters, J. Mater. Chem. B 9 (2021) 307-313, doi: 10.1039/d0tb02267e.

[125] Q. Yu, T. Deng, F.C. Lin, B. Zhang, J.I. Zink, Supramolecular assemblies of heterogeneous mesoporous silica nanoparticles to Co—deliver antimicrobial peptides and antibiotics for synergistic eradication of pathogenic biofilms, ACS Nano 14 (2020) 5926-5937, doi: 10.1021/acsnano.0c01336.

[126] Z. Cui, Y. Li, Y. Qin, J. Li, L. Shi, M. Wan, M. Hu, Y. Chen, Y. Ji, Y. Hou, C. Liu, F. Ye, Polymyxin B—targeted liposomal photosensitizer cures MDR A. baumannii burn infections and accelerates wound healing via M1/M2 macrophage polarization, J. Control. Rel. 366 (2024) 297-311, doi: 10.1016/j.jconrel.2023.12.046.

[127] X. Lai, S.H. Chow, A.P. Le Brun, B.W. Muir, P.J. Bergen, J. White, H.H. Yu, J. Wang, J. Danne, J. hang Jiang, F.L. Short, M.L. Han, R.A. Strugnell, J. Song, N.R. Cameron, A.Y. Peleg, J. Li, H.H. Shen, Polysaccharide—targeting lipid nanoparticles to kill gram—negative bacteria, Small 20 (2024) 1-13, doi: 10.1002/smll.202305052.

[128] B. Casciaro, I. Angelo, X. Zhang, M. Rosa, G. Conte, F. Cappiello, F. Quaglia, Y.P. Di, F. Ungaro, M.L. Mangoni, Poly(lactide—co—glycolide) nanoparticles for prolonged therapeutic Efficacy of esculentin—1a—derived antimicrobial peptides against Pseudomonas aeruginosa lung infection: in Vitro and in Vivo studies , Biomacromolecules 20 (2019) 1876-1888, doi: 10.1021/acs.biomac.8b01829.

[129] V. Laverde—Rojas, Y. Liscano, S.P. Rivera—Sánchez, I.D. Ocampo—Ibáñez, Y. Betancourt, M.J. Alhajj, C.J. Yarce, C.H. Salamanca, J. Oñate—Garzón, Antimicrobial contribution of chitosan surface—modified nanoliposomes combined with colistin against sensitive and colistin—resistant clinical Pseudomonas aeruginosa, Pharmaceutics 13 (2021) 41, doi: 10.3390/pharmaceutics13010041.

[130] J.J. Ahire, L.M.T. Dicks, Nisin incorporated with 2,3—dihydroxybenzoic acid in nanofibers inhibits biofilm formation by a methicillin—resistant strain of Staphylococcus aureus, Probiot. Antimicrob. Prot. 7 (2015) 52-59, doi: 10.1007/s12602—014—9171—5.

[131] J.J. Ahire, D.P. Neveling, L.M.T. Dicks, Co—spinning of silver nanoparticles with nisin increases the antimicrobial spectrum of PDLLA: PEO nanofibers, Curr. Microbiol. 71 (2015) 24-30, doi: 10.1007/s00284—015—0813—y.

[132] Y.K. Mohanta, I. Chakrabartty, A.K. Mishra, H. Chopra, S. Mahanta, S.K. Avula, K. Patowary, R. Ahmed, B. Mishra, T.K. Mohanta, M. Saravanan, N. Sharma, Nanotechnology in combating biofilm: a smart and promising therapeutic strategy, Front. Microbiol. 13 (2022) 1-30, doi: 10.3389/fmicb.2022.1028086.

[133] M. Ramasamy, J. Lee, Recent nanotechnology approaches for prevention and treatment of biofilm—associated infections on medical devices, Biomed Res. Int. 2016 (2016) 1-17, doi: 10.1155/2016/1851242.

[134] Y. Zhou, W. Deng, M. Mo, D. Luo, H. Liu, Y. Jiang, W. Chen, C. Xu, Stimuli—responsive nanoplatform—assisted photodynamic therapy against bacterial infections, Front. Med. 8 (2021) 1-8, doi: 10.3389/fmed.2021.729300.

[135] X. Wang, M. Shan, S. Zhang, X. Chen, W. Liu, J. Chen, X. Liu, Stimuli—responsive antibacterial materials: molecular structures, design principles, and biomedical applications, Adv. Sci. 9 (2022) 1-25, doi: 10.1002/advs.202104843.

[136] M. Blanco Massani, D. To, S. Meile, M. Schmelcher, D. Gintsburg, D.C. Coraça—Huber, A. Seybold, M. Loessner, A. Bernkop—Schnürch, Enzyme—responsive nanoparticles: enhancing the ability of endolysins to eradicate Staphylococcus aureus biofilm, J. Mater. Chem. B 12 (2024) 9199-9205, doi: 10.1039/d4tb01122h.

[137] Y. Guo, Z. Mao, F. Ran, J. Sun, J. Zhang, G. Chai, J. Wang, Nanotechnology—based drug delivery systems to control bacterial—biofilm—associated lung infections, Pharmaceutics 15 (2023) 2582, doi: 10.3390/pharmaceutics15112582.

[138] X. Chen, Z. Lin, N. Cheng, Y. Mo, L. Lu, J. Hou, Z. Li, X. Nie, S. Gao, Q. Hua, Recent advances in NIR—II photothermal and photodynamic therapies for drug—resistant wound infections, Mater. Today Bio 32 (2025) 101871, doi: 10.1016/j.mtbio.2025.101871.

[139] Y. Ren, H. Liu, X. Liu, Y. Zheng, Z. Li, C. Li, K.W.K. Yeung, S. Zhu, Y. Liang, Z. Cui, S. Wu, Photoresponsive materials for antibacterial applications, Cell Rep. Phys. Sci. 1 (2020) 100245, doi: 10.1016/j.xcrp.2020.100245.

[140] I. Wiegand, K. Hilpert, R.E.W. Hancock, Agar and broth dilution methods to determine the minimal inhibitoryconcentration (MIC) of antimicrobialsubstances, Nat. Protoc. 3 (2008) 163-175, doi: 10.1038/nprot.2007.521.

[141] P. Brasil, G.A. Calvet, A.M. Siqueira, M. Wakimoto, P.C. de Sequeira, A. Nobre, M. de, S.B. Quintana, M.C.L. de M endonça, O. Lupi, R.V. de Souza, C. Romero, H. Zogbi, C. da, S. Bressan, S.S. Alves, R. Lourenço—de—Oliveira, R.M.R. Nogueira, M.S. Carvalho, A.M.B. de Filippis, T. Jaenisch, Zika virus outbreak in Rio de Janeiro, Brazil: clinical characterization, epidemiological and virological aspects, PLoS Negl. Trop. Dis. 10 (2016) e0004636, doi: 10.1371/journal.pntd.0004636.

[142] C.G. Starr, W.C. Wimley, Antimicrobial peptides are degraded by the cytosolic proteases of human erythrocytes, Biochim. Biophys. Acta — Biomembr. 1859 (2017) 2319-2326, doi: 10.1016/j.bbamem.2017.09.008.

[143] A. De Breij, E.M. Haisma, M. Rietveld, A. El Ghalbzouri, P.J. Van Den Broek, L. Dijkshoorn, P.H. Nibbering, Three—dimensional human skin equivalent as a tool to study Acinetobacter baumannii colonization, Antimicrob. Agents Chemother. 56 (2012) 2459-2464, doi: 10.1128/AAC.05975—11.

[144] J. Gloede, C. Scheerans, H. Derendorf, C. Kloft, In vitro pharmacodynamic models to determine the effect of antibacterial drugs , J. Antimicrob. Chemother. 65 (2010) 186-201, doi: 10.1093/jac/dkp434.

[145] B.K.H.L. Boekema, L. Pool, M.M.W. Ulrich, The effect of a honey based gel and silver sulphadiazine on bacterial infections of in vitro burn wounds , Burns 39 (2013) 754-759, doi: 10.1016/j.burns.2012.09.008.

[146] T. Komprda, Z. Sládek, M. Vícenová, J. Simonová, G. Franke, B. Lipový, M. Matejovičová, K. Kacvinská, C. Sabliov, C.E. Astete, L. Levá, V. Popelková, A. Bátik, L. Vojtová, Effect of polymeric nanoparticles with entrapped fish oil or mupirocin on skin wound healing using a porcine model, Int. J. Mol. Sci. 23 (2022) 7663, doi: 10.3390/ijms23147663.

[147] F. Raška, B. Lipový, Š. Kobzová, L. Vacek, R. Jarošová, D. Kleknerová, K. Matiašková, P. Makovický, M. Vícenová, E. Jeklová, R. Pantůček, M. Faldyna, L. Janda, Development of a porcine model of skin and soft—tissue infection caused by Staphylococcus aureus, including methicillin—resistant strains suitable for testing topical antimicrobial agents, Anim. Model. Exp. Med. 8 (2025) 544-557, doi: 10.1002/ame2.12495.

[148] A. Semaniakou, R.P. Croll, V. Chappe, Animal models in the pathophysiology of cystic fibrosis, Front. Pharmacol. 9 (2019) 1-16, doi: 10.3389/fphar.2018.01475.

[149] A. Kroll, M.H. Pillukat, D. Hahn, J. Schnekenburger, Current in vitro methods in nanoparticle risk assessment: limitations and challenges , Eur. J. Pharm. Biopharm. 72 (2009) 370-377, doi: 10.1016/j.ejpb.2008.08.009.

[150] A. Khan, M. Xu, T. Wang, C. You, X. Wang, H. Ren, H. Zhou, A. Khan, C. Han, P. Li, Catechol cross—linked antimicrobial peptide hydrogels prevent multidrug—resistant Acinetobacter baumannii infection in burn wounds, Biosci. Rep. 39 (2019) 1-15, doi: 10.1042/BSR20190504.

[151] S. Nithya, T.R. Nimal, G. Baranwal, M.K. Suresh, C.P. Anju, V. Anil Kumar, C. Gopi Mohan, R. Jayakumar, R. Biswas, Preparation, characterization and efficacy of lysostaphin—chitosan gel against Staphylococcus aureus, Int. J. Biol. Macromol. 110 (2018) 157-166, doi: 10.1016/j.ijbiomac.2018.01.083.

[152] R. Thaya, B. Malaikozhundan, S. Vijayakumar, J. Sivakamavalli, R. Jeyasekar, S. Shanthi, B. Vaseeharan, P. Ramasamy, A. Sonawane, Chitosan coated Ag/ZnO nanocomposite and their antibiofilm, antifungal and cytotoxic effects on murine macrophages, Microb. Pathog. 100 (2016) 124-132, doi: 10.1016/j.micpath.2016.09.010.

[153] S. Obuobi, Z.X. Voo, M.W. Low, B. Czarny, V. Selvarajan, N.L. Ibrahim, Y.Y. Yang, P.L.R. Ee, Phenylboronic acid functionalized polycarbonate hydrogels for controlled release of polymyxin B in Pseudomonas Aeruginosa infected burn wounds, Adv. Healthc. Mater. 7 (2018) 1-8, doi: 10.1002/adhm.201701388.

[154] A.C. Anselmo, M. Zhang, S. Kumar, D.R. Vogus, S. Menegatti, M.E. Helgeson, S. Mitragotri, Elasticity of nanoparticles Influences, ACS Nano 9 (2015) 3169-3177.

[155] A. Scheeder, M. Brockhoff, E.N. Ward, G.S. Kaminski Schierle, I. Mela, C.F. Kaminski, Molecular mechanisms of cationic fusogenic liposome interactions with bacterial envelopes, J. Am. Chem. Soc. 145 (2023) 28240-28250, doi: 10.1021/jacs.3c11463.

[156] M.A.J. Shaikh, K. Goyal, M. Afzal, R. Roopashree, M. Kumari, T. Krithiga, R. Panigrahi, S. Saini, H. Ali, M. Imran, T.P. Abida, G. Gupta, Liposome—encapsulated therapies: precision medicine for inflammatory lung disorders, Nano TransMed 4 (2025) 100082, doi: 10.1016/j.ntm.2025.100082.

[157] J. Palacio, Y. Monsalve, J.A. Villa—Pulgarin, K.V. Contreras Ramirez, C.E.N. Chica, L. Sierra, B.L. López, Preparation and evaluation of PLGA—PEG/Gusperimus nanoparticles as a controlled delivery anti—inflammatory drug, J. Drug Deliv. Sci. Technol. 77 (2022) 103889, doi: 10.1016/j.jddst.2022.103889.

[158] D. Venturoli, B. Rippe, Ficoll and dextran vs. globular proteins as probes for testing glomerular permselectivity: effects of molecular size, shape, charge, and deformability , Am. J. Physiol. — Ren. Physiol. 288 (2005) F605-F613, doi: 10.1152/ajprenal.00171.2004.

[159] N. Raman, M.R. Lee, S.P. Palecek, D.M. Lynn, Polymer multilayers loaded with antifungal β—peptides kill planktonic Candida albicans and reduce formation of fungal biofilms on the surfaces of flexible catheter tubes , J. Control. Rel. 191 (2014) 54-62, doi: 10.1016/j.jconrel.2014.05.026.

[160] Y.X. Li, H.B. Wang, J. Li, J.B. Jin, J.B. Hu, C.L. Yang, Targeting pulmonary vascular endothelial cells for the treatment of respiratory diseases, Front. Pharmacol. 13 (2022) 1-15, doi: 10.3389/fphar.2022.983816.

[161] Y.Y. Liu, J. Liu, H. Wu, Q. Zhang, X.R. Tang, D. Li, C.S. Li, Y. Liu, A. Cao, H. Wang, Endocytosis, distribution, and exocytosis of polystyrene nanoparticles in Human lung cells, Nanomaterials 13 (2023) 84, doi: 10.3390/nano13010084.

[162] W.H. De Jong, P.J.A. Borm, Drug delivery and nanoparticles: applications and hazards, Int. J. Nanomedicine 3 (2008) 133, doi: 10.2147/ijn.s596.

[163] A. Areny—Balagueró, W. Mekseriwattana, M. Camprubí—Rimblas, A. Stephany, A. Roldan, A. Solé—Porta, A. Artigas, D. Closa, A. Roig, Fluorescent PLGA nanocarriers for pulmonary administration: influence of the surface charge, Pharmaceutics 14 (2022) 1447, doi: 10.3390/pharmaceutics14071447.

[164] P. Kattel, S. Sulthana, J. Trousil, D. Shrestha, D. Pearson, S. Aryal, Effect of nanoparticle weight on the cellular uptake and drug delivery potential of PLGA nanoparticles, ACS Omega 8 (2023) 27146-27155, doi: 10.1021/acsomega.3c02273.

[165] H. Pang, W. Yu, Y. Wu, X. Nie, G. Huang, Z.P. Xu, C. Chen, F.Y. Han, Enhanced epithelial cell uptake of glycol chitosan—coated PLGA nanoparticles for oral drug delivery, Adv. Ther. 8 (2025) 1-11, doi: 10.1002/adtp.202400547.

[166] S.J. Huang, T.H. Wang, Y.H. Chou, H.M.D. Wang, T.C. Hsu, J. Le Yow, B.S. Tzang, W.H. Chiang, Hybrid PEGylated chitosan/PLGA nanoparticles designed as pH—responsive vehicles to promote intracellular drug delivery and cancer chemotherapy, Int. J. Biol. Macromol. 210 (2022) 565-578, doi: 10.1016/j.ijbiomac.2022.04.209.

[167] K. Forier, K. Raemdonck, S.C. De Smedt, J. Demeester, T. Coenye, K. Braeckmans, Lipid and polymer nanoparticles for drug delivery to bacterial biofilms, J. Control. Release 190 (2014) 607-623, doi: 10.1016/j.jconrel.2014.03.055.

[168] S. Dhanam, N. Rameshkumar, M. Krishnan, Comparative assessment of bacteriocin and bacteriocin capped nanoparticles in mice model, Mater. Lett. 313 (2022) 131740, doi: 10.1016/j.matlet.2022.131740.

[169] E. Sans—Serramitjana, E. Fusté, B. Martínez—Garriga, A. Merlos, M. Pastor, J.L. Pedraz, A. Esquisabel, D. Bachiller, T. Vinuesa, M. Viñas, Killing effect of nanoencapsulated colistin sulfate on Pseudomonas aeruginosa from cystic fibrosis patients, J. Cyst. Fibros. 15 (2016) 611-618, doi: 10.1016/j.jcf.2015.12.005.

[170] N. Changsan, A. Atipairin, P. Sakdiset, P. Muenraya, N. Balekar, T. Srichana, R. Sritharadol, S. Phanapithakkun, S. Sawatdee, BrSPR—20—P1 peptide isolated from brevibacillus sp. developed into liposomal hydrogel as a potential topical antimicrobial agent, RSC Adv. 14 (2024) 27394-27411, doi: 10.1039/d4ra03722g.

[171] M. Ali, X.F. Walboomers, J.A. Jansen, F. Yang, Influence of formulation parameters on encapsulation of doxycycline in PLGA microspheres prepared by double emulsion technique for the treatment of periodontitis, J. Drug Deliv. Sci. Technol. 52 (2019) 263-271, doi: 10.1016/j.jddst.2019.04.031.

[172] W. Yu, J. Guo, Y. Liu, X. Xue, X. Wang, L. Wei, J. Ma, Potential impact of combined inhibition by bacteriocins and chemical substances of foodborne pathogenic and spoilage bacteria: a review, Foods 12 (2023) 3128, doi: 10.3390/foods12163128.

[173] Y. Wei, Y. Li, X. Li, Y. Zhao, J. Xu, H. Wang, X. Rong, J. Xiong, X. Chen, G. Luo, G. Lv, C. Lin, C. Han, H. Yu, Y. Zhang, S. Tang, Y. Fan, J. Tu, C. Xia, H. Zu, W. Liu, C. Liu, J. Liu, B. Zhang, Q. Nong, T. Li, L. Wang, G. Song, Y. Su, Z. Chen, W. Lai, Y. Fu, J. Yu, P. Zhang, W. Yang, G. Yao, H. Zhang, K. Fan, H. Dong, Y. Chen, J. Wu, Peceleganan spray for the treatment of skin wound infections: a randomized clinical trial, JAMA Netw. Open 7 (2024) e2415310, doi: 10.1001/jamanetworkopen.2024.15310.

[174] K. Browne, S. Chakraborty, R. Chen, M.D.P. Willcox, D.S. Black, W.R. Walsh, N. Kumar, A new era of antibiotics: the clinical potential of antimicrobial peptides, Int. J. Mol. Sci. 21 (2020) 7047, doi: 10.3390/ijms21197047.

[175] E.M. Bulger, A.K. May, B.R.H. Robinson, D.C. Evans, S. Henry, J.M. Green, E. Toschlog, J.L. Sperry, P. Fagenholz, N.D. Martin, W.M. Dankner, G. Maislin, D. Wilfret, A.C. Bernard, A novel immune modulator for patients with necrotizing soft tissue infections (NSTI): results of a multicenter, phase 3 randomized controlled trial of Reltecimod (AB 103), Ann. Surg. 272 (2020) 469-478, doi: 10.1097/SLA.0000000000004102.

[176] E.A. Ismail, V.O. Nyandoro, C.A. Omolo, T. Govender, Nanocarrier—based targeting of pattern recognition receptors as an innovative strategy for enhancing sepsis therapy, Adv. Healthc. Mater. 14 (2025), doi: 10.1002/adhm.202501146.

[177] Z. Omrani, M. Pourmadadi, A. Rahdar, S. Ghotekar, Recent advances in cefixime—loaded nanomaterials for treating bacterial infections, Bionanoscience 15 (2025) 467, doi: 10.1007/s12668—025—02087—y.

[178] V.O. Nyandoro, E.A. Ismail, A. Tageldin, M.A. Gafar, X.Q. Peters, R. Mautsoe, C.A. Omolo, T. Govender, Potential of nanocarrier—mediated delivery of vancomycin for MRSA infections, Expert Opin. Drug Deliv. 22 (2025) 347-365, doi: 10.1080/17425247.2025.2459756.

[179] J. Han, J. Meade, D. Devine, A. Sadeghpour, M. Rappolt, F.M. Goycoolea, Chitosan—coated liposomal systems for delivery of antibacterial peptide LL17—32 to Porphyromonas gingivalis, Heliyon 10 (2024) e34554, doi: 10.1016/j.heliyon.2024.e34554.

[180] G. Wang, J.L. Narayana, B. Mishra, Y. Zhang, F. Wang, C. Wang, D. Zarena, T. Lushnikova, X. Wang, Design of antimicrobial peptides: progress made with Human Cathelicidin LL—37, Antimicrob. Pept. Basics Clin. Appl. (2019) 215-240, doi: 10.1007/978—981—13—3588—4_12.

[181] Y. Zhu, W. Xu, W. Chen, B. Li, G. Li, H. Deng, L. Zhang, C. Shao, A. Shan, Self—assembling peptide with dual function of cell penetration and antibacterial as a nano weapon to combat intracellular bacteria, Sci. Adv. 11 (2025) 1-19, doi: 10.1126/sciadv.ads3844.

[182] S. Deo, K.L. Turton, T. Kainth, A. Kumar, H.J. Wieden, Strategies for improving antimicrobial peptide production, Biotechnol. Adv. 59 (2022) 107968, doi: 10.1016/j.biotechadv.2022.107968.

[183] P.E. Saw, E.W. Song, Phage display screening of therapeutic peptide for cancer targeting and therapy, Protein Cell 10 (2019) 787-807, doi: 10.1007/s13238—019—0639—7.

[184] G.Y. Liu, D. Yu, M.M. Fan, X. Zhang, Z.Y. Jin, C. Tang, X.F. Liu, Antimicrobial resistance crisis: could artificial intelligence be the solution? Mil. Med. Res. 11 (2024) 1-23, doi: 10.1186/s40779—024—00510—1.

[185] J. Huang, Y. Xu, Y. Xue, Y. Huang, X. Li, X. Chen, Y. Xu, D. Zhang, P. Zhang, J. Zhao, J. Ji, Identification of potent antimicrobial peptides via a machine—learning pipeline that mines the entire space of peptide sequences, Nat. Biomed. Eng. 7 (2023) 797-810, doi: 10.1038/s41551—022—00991—2.

[186] J.R. Randall, L.C. Vieira, C.O. Wilke, B.W. Davies, Deep mutational scanning and machine learning for the analysis of antimicrobial—peptide features driving membrane selectivity, Nat. Biomed. Eng. 8 (2024) 842-853, doi: 10.1038/s41551—024—01243—1.

[187] M.C.R. Melo, J.R.M.A. Maasch, C. de la Fuente—Nunez, Accelerating antibiotic discovery through artificial intelligence, Commun. Biol. 4 (2021) 1-13, doi: 10.1038/s42003—021—02586—0.

[188] Y. Wang, L. Wang, C. Li, Y. Pei, X. Liu, Y. Tian, AMP—EBiLSTM: employing novel deep learning strategies for the accurate prediction of antimicrobial peptides, Front. Genet. 14 (2023) 1-14, doi: 10.3389/fgene.2023.1232117.

[189] M. Salem, A. Keshavarzi Arshadi, J.S. Yuan, AMPDeep: hemolytic activity prediction of antimicrobial peptides using transfer learning, BMC Bioinform. 23 (2022) 1-17, doi: 10.1186/s12859—022—04952—z.

[190] J. Xu, F. Li, C. Li, X. Guo, C. Landersdorfer, H.H. Shen, A.Y. Peleg, J. Li, S. Imoto, J. Yao, T. Akutsu, J. Song, iAMPCN: a deep—learning approach for identifying antimicrobial peptides and their functional activities, Brief. Bioinform. 24 (2023) 1-20, doi: 10.1093/bib/bbad240.

[191] S. Lata, N.K. Mishra, G.P.S. Raghava, AntiBP2: improved version of antibacterial peptide prediction, BMC Bioinform. 11 (2010) 1-7, doi: 10.1186/1471—2105—11—S1—S19.

[192] A.J. Pereira, L.J. de Campos, H. Xing, M. Conda—Sheridan, Peptide—based therapeutics: challenges and solutions, Med. Chem. Res. 33 (2024) 1275-1280, doi: 10.1007/s00044—024—03269—1.

[193] D. Simberg, S.M. Moghimi, Complement activation by nanomaterials, 2020. https://doi.org/10.1007/978—3—030—33962—3_6.

[194] N.M. La—Beck, M.R. Islam, M.M. Markiewski, Nanoparticle—induced complement activation: implications for cancer nanomedicine, Front. Immunol. 11 (2021) 1-12, doi: 10.3389/fimmu.2020.603039.

[195] A.A. Aljabali, M.A. Obeid, R.M. Bashatwah, Á. Serrano—Aroca, V. Mishra, Y. Mishra, M. El—Tanani, A. Hromić—Jahjefendić, D.N. Kapoor, R. Goyal, G.A. Naikoo, M.M. Tambuwala, Nanomaterials and their impact on the immune system, Int. J. Mol. Sci. 24 (2023) 2008, doi: 10.3390/ijms24032008.

[196] D.E. Uti, E.U. Alum, I.J. Atangwho, O.P.C. Ugwu, G.E. Egbung, P.M. Aja, Lipid—based nano—carriers for the delivery of anti—obesity natural compounds: advances in targeted delivery and precision therapeutics, J. Nanobiotechnol. 23 (2025), doi: 10.1186/s12951—025—03412—z.

[197] Y. Zhu, M. He, C. Lin, W. Ma, Y. Ai, J. Wang, Q. Liang, Multifunctional nanocarrier drug delivery systems: from diverse design to precise biomedical applications, Adv. Healthc. Mater. 15 (2026), doi: 10.1002/adhm.202502178.

[198] M.A. Younis, H.M. Tawfeek, A.A.H. Abdellatif, J.A. Abdel—Aleem, H. Harashima, Clinical translation of nanomedicines: challenges, opportunities, and keys, Adv. Drug Deliv. Rev. 181 (2022) 114083, doi: 10.1016/j.addr.2021.114083.

[199] Z. Su, H. Yu, T. Lv, Q. Chen, H. Luo, H. Zhang, Progress in the classification, optimization, activity, and application of antimicrobial peptides, Front. Microbiol. 16 (2025) 1-20, doi: 10.3389/fmicb.2025.1582863.

[200] S. Liu, R. Wang, L. Li, X. Wang, J. Gong, X. Liu, Z. Song, L. Sun, X. Liu, W. Ning, Y. Song, S.—Y. Fung, H. Yang, Designer amphiphilic helical peptide—decorated nanomicelles enable simultaneous inflammation control and triple—destruction of bacteria for treating bacterial pneumonia and sepsis, Theranostics 15 (2025) 9047-9072, doi: 10.7150/thno.110538.

[201] Y.P. Di, J.M. Kuhn, M.L. Mangoni, Lung antimicrobial proteins and peptides: from host defense to therapeutic strategies, Physiol. Rev. 104 (4) (2024) 1643-1677, doi: 10.1152/physrev.00039.2023.

[202] M.E. van Gent, M. Ali, P.H. Nibbering, S.N. Klodzińska, Current advances in lipid and polymeric antimicrobial peptide delivery systems and coatings for the prevention and treatment of bacterial infections, Pharmaceutics 13 (11) (2021) 1840, doi: 10.3390/pharmaceutics13111840.