Functional insights to the development of bioactive material for combating bacterial infections

The paper addresses the urgent need for new antibacterial strategies due to escalating antimicrobial resistance, driven by mechanisms such as efflux pumps and rapid mutation of single targets that undermine traditional small-molecule antibiotics. It focuses on bioactive materials—especially cationic polymers and nanomaterials—as next-generation agents capable of combating drug-resistant bacteria and biofilms. The review outlines how these materials can act via membrane disruption, reactive oxygen species generation, photothermal/photodynamic effects, and as delivery platforms, with the goal of improving efficacy, selectivity, stability, and reducing resistance development.

The review surveys antimicrobial mechanisms and design strategies for cationic polymers and diverse nanomaterials against planktonic and biofilm-associated bacteria. Mechanisms: Cationic polymers (including AMPs and synthetic analogs) exploit amphiphilicity and positive charge to bind and disrupt bacterial membranes in Gram-positive and Gram-negative species; some penetrate cells to inhibit DNA/RNA/protein synthesis and enzymatic processes. Metallic/metal oxide nanoparticles employ electrostatic adhesion to bacterial surfaces, ion release (e.g., Ag+, Cu2+), ROS generation, ATP synthesis inhibition, and ribosomal interference. Light-activated modalities include photodynamic therapy (type I/II ROS generation) and photothermal therapy with NIR-absorbing agents boasting strong absorption, low fluorescence yield, dark biocompatibility, and fast clearance. Cationic polymers: Amphiphilic frameworks (e.g., RAFT-made SCNPs) showed strong anti-planktonic and antibiofilm effects; Nguyen et al. (2017) reported >99% eradication of planktonic and biofilm bacteria within 1 h at micromolar levels. Takahashi et al. (2017) synthesized cationic PE0 and PE31 (31% ethyl methacrylate) that killed S. mutans and reduced biofilm biomass by ~80% at 1000 μg/mL within 2 h. AMP-mimicking bile-acid polymers achieved broad-spectrum activity with low hemolysis (Rahman et al., 2018; 2020). Biocompatible POX-based Gly-POX peptidomimetics via CROP were effective against MRSA biofilms in vitro/in vivo (Zhou et al., 2020). Stimuli-responsive systems: pH-responsive conjugates (Ye et al., 2020) released cationic polymers at infection sites with low MICs and low hemolysis. Charge-switchable coatings (QPEI; Hoque et al., 2019) toggled between cationic/zwitterionic states to kill bacteria and suppress biofilms with low toxicity. Charge-switchable micelles (Chen et al., 2021) enhanced biofilm penetration and delivered azithromycin. Additional strategies include peptidomimetic polyurethanes that enhance bacterial motility and disrupt biofilms at subinhibitory doses (Vishwakarma et al., 2021) and polysaccharide-based DA95B5 nanoparticles that disperse biofilms to sensitize bacteria (Li et al., 2018a). Chitosan-based polymers: Adhesive, stretchable hydrogels (Qu et al., 2018) provided in vivo antibiofilm efficacy; quaternary ammonium chitosan-liposome-doxycycline nanoparticles targeted oral biofilms with good biocompatibility (Hu et al., 2019). pH-sensitive cysteine-conjugated chitosan/PMLA nanoparticles delivered amoxicillin to H. pylori with low mammalian toxicity (Arif et al., 2018). AMPs: AIE-tagged AMPs enable imaging of AMP–bacteria interactions (Chen et al., 2018; Bao et al., 2021; Feng et al., 2015). AMP-containing hydrogels (e.g., HA-AMP/ODEX; Wei et al., 2021) showed broad-spectrum antibacterial action and promoted wound healing; DP7 hydrogels synergized with ceftazidime to overcome Gram-negative outer membranes and biofilms (Wu et al., 2022). Surface-immobilized AMPs on hydrogels and medical devices provided bactericidal activity with low hemolysis (Cleophas et al., 2014a,b; Liu et al., 2021). Encapsulation in nanoparticles reduced AMP cytotoxicity and enhanced efficacy (Sharma et al., 2018; 2021; Salama, 2022). CPP conjugation improved AMP penetration and activity (Lee et al., 2019a; Li et al., 2018b). AMP-coated implants demonstrated rapid and sustained release with antibiofilm benefits without impairing osseointegration (Kazemzadeh-Narbat et al., 2012; 2013; Abbasizadeh et al., 2020; Miao et al., 2021). Nanomaterials: Metal/metal oxide nanoparticles. AgNPs’ activity is governed by Ag+ release; controlled release composites like DATNFC@Ag achieved 10.06% cumulative Ag+ in 32 days with a modelled long-term release (Li et al., 2019), providing extended antibacterial action. CuNPs and Ag–Cu bimetallics offer broad-spectrum action and improved efficacy (Jin et al., 2023). AuNPs act via membrane potential collapse, ATP depletion, and ribosomal tRNA binding without ROS (Cui et al., 2012); tunable A/M-AuNPs displayed potent activity with high safety margins and antibiofilm effects (Wang et al., 2021a). AuNPs/AuNCs also serve as photothermal agents for NIR-triggered biofilm ablation (Hu et al., 2017). ZnONPs show strong antibacterial activity; chitosan-coated ZnO with rutin improved efficacy (Bharathi et al., 2019). ZnO sputtered onto titanium promoted antibacterial activity and immune activation in vivo. Polymeric nanoparticles: pH-responsive chitosan nanoparticles released vancomycin in acidic infection microenvironments (Kalhapure et al., 2017). β-cyclodextrin nanoparticles improved the antibacterial potential of naringin (Hussain et al., 2022). Amphiphilic peptide nanoparticles exhibited strong inherent antimicrobial activity and blood-brain barrier penetration (Liu et al., 2009). Polymeric micelles eradicated MDR biofilms (Landis et al., 2017) and enabled combined AgNPs-curcumin delivery with synergy and biocompatibility (Huang et al., 2017). Other nanomaterials: Liposomes improved MIC/MBIC of encapsulated antibiotics against biofilms (Forier et al., 2014), enhanced intracellular drug accumulation (~40-fold for enrofloxacin SLNs; Xie et al., 2017), and cationic liposomes displayed intrinsic antibacterial activity (Laune et al., 2022). Nanoemulsions stabilized essential oils to enhance stability and broaden antibacterial spectra (Mazarei and Rafati, 2019; Yazgan et al., 2019; Prakash et al., 2019; Lee et al., 2019b; Farahani et al., 2020). Microneedles delivered antimicrobials (e.g., AgNPs, Zn-MOFs, AMPs), promoting wound healing and antibiofilm action with minimal invasiveness (García et al., 2018; Chi et al., 2020; Yao et al., 2021; Su et al., 2020; Gao et al., 2021; Deng et al., 2022; Shi et al., 2023).

- Cationic polymers and AMPs: Amphiphilic, positively charged polymers disrupt bacterial membranes and, in some cases, inhibit intracellular targets. RAFT-synthesized SCNPs eradicated >99% planktonic and biofilm bacteria within 1 h at micromolar concentrations (Nguyen et al., 2017). Cationic polymers PE0/PE31 reduced S. mutans biofilm biomass by ~80% at 1000 μg/mL within 2 h (Takahashi et al., 2017). Bile-acid-based amphiphilic polymers achieved broad-spectrum activity with low hemolysis (Rahman et al., 2018; 2020). Poly(2-oxazoline)-based peptidomimetics showed potent in vitro and in vivo efficacy against MRSA-biofilm infection (Zhou et al., 2020). - Stimuli-responsive systems: pH-responsive polymer–drug conjugates (streptomycin–polyurea via imine bonds) enabled charge reversal and on-demand release at infection sites, exhibiting low MICs against multiple pathogens and low hemolysis (Ye et al., 2020). Charge-switchable coatings (QPEI) and micelles (PLA-PEI-hyd-mPEG) targeted acidic biofilm niches, improved penetration, and demonstrated in vivo antibiofilm efficacy while reducing toxicity (Hoque et al., 2019; Chen et al., 2021). - Biofilm management: Peptidomimetic polyurethanes prevented attachment and disrupted established biofilms at sub-MICs (Vishwakarma et al., 2021). DA95B5 block copolymer nanoparticles dispersed Gram-positive biofilms, enabling subsequent antibiotic susceptibility (Li et al., 2018a). - Chitosan-based platforms: Adhesive curcumin-loaded hydrogels displayed skin-like stretchability (58.2%–76.1%) and strong in vivo antibiofilm efficacy (Qu et al., 2018). TMC-liposome–doxycycline nanoparticles targeted oral biofilms with good biocompatibility (Hu et al., 2019). Cysteine-conjugated chitosan/PMLA nanoparticles delivered amoxicillin to H. pylori with minimal mammalian cytotoxicity (Arif et al., 2018). - AMPs in hydrogels/coatings: HA-AMP/ODEX hydrogels provided broad-spectrum antibacterial activity and accelerated wound healing (Wei et al., 2021); DP7 + ceftazidime hydrogels synergized against P. aeruginosa and biofilms (Wu et al., 2022). AMP-coated implants achieved rapid then sustained release, preventing S. aureus and P. aeruginosa biofilms without hindering bone growth (Kazemzadeh-Narbat et al., 2012; 2013). Nanocarrier-encapsulated AMPs reduced cytotoxicity and enhanced antimicrobial synergy (Sharma et al., 2018; 2021; Salama, 2022). CPP conjugation boosted AMP efficacy (2–16× increases) (Lee et al., 2019a). - Metal/metal oxide nanoparticles: AgNPs’ antibacterial activity correlates with controlled Ag+ release; DATNFC@Ag released 10.06% Ag+ over 32 days, enabling projected long-term effects (Li et al., 2019). Ag–Cu alloy nanoclusters yielded 30%–53% improved antibacterial performance and complete bactericidal behavior (Jin et al., 2023). AuNPs operated via non-ROS mechanisms (membrane potential collapse, ATP depletion; ribosomal interference) and achieved high safety margins; A/M-AuNPs disrupted biofilms (Cui et al., 2012; Wang et al., 2021a). NIR-activated AuNPs increased local temperature by ~28°C to ablate MRSA biofilms without damaging nearby tissues (Hu et al., 2017). ZnONPs exhibited strong antibacterial activity; surface modification (e.g., chitosan/rutin) improved efficacy and biocompatibility, and ZnO coatings on implants enhanced in vivo anti-infective outcomes via immune activation. - Polymeric nanoparticles/micelles: pH-responsive CSNPs delivered vancomycin in acidic environments (Kalhapure et al., 2017). β-cyclodextrin naringin nanoparticles improved membrane destabilization and antibacterial effect (Hussain et al., 2022). Amphiphilic peptide nanoparticles showed intrinsic antimicrobial activity and BBB penetration (Liu et al., 2009). Cross-linked micelles (~250 nm) and AgNP–curcumin micelles eradicated MDR biofilms and showed synergy with low hemolysis (Landis et al., 2017; Huang et al., 2017). - Other nanomaterials: Liposomes enhanced antibiotic delivery to biofilms and intracellular bacteria (Forier et al., 2014; Xie et al., 2017), while cationic liposomes displayed inherent antibacterial action (Laune et al., 2022). Nanoemulsions stabilized essential oils, increasing stability and antibacterial spectrum across foodborne pathogens (Mazarei and Rafati, 2019; Yazgan et al., 2019; Prakash et al., 2019; Lee et al., 2019b). Microneedles enabled minimally invasive delivery of antimicrobials (e.g., AgNPs, Zn-MOFs, AMPs), improving wound healing and anti-biofilm outcomes (García et al., 2018; Chi et al., 2020; Yao et al., 2021; Su et al., 2020).

The review consolidates evidence that cationic polymers and nanomaterials provide complementary and synergistic approaches to address bacterial infections, particularly those involving multidrug resistance and biofilms. By leveraging electrostatic interactions, amphiphilicity, and stimuli-responsiveness, cationic polymers can achieve rapid membrane disruption, enhanced biofilm penetration, and on-demand activation in infection microenvironments. Nanomaterials broaden the therapeutic arsenal by facilitating multiple mechanisms—ion release (Ag+, Cu2+), metabolic disruption, ROS generation (PDT), and localized heating (PTT)—and by serving as versatile carriers that improve pharmacokinetics, targeting, and intracellular delivery. Quantitative studies demonstrate high levels of bacterial eradication, significant biofilm biomass reduction, and enhanced intracellular killing. Device-related infection mitigation through AMP-functional coatings and NP-modified surfaces illustrates translational potential. However, concerns remain regarding off-target cytotoxicity, immunogenicity, long-term stability, and aggregation of metallic NPs. The field is moving toward integrated platforms combining multiple bactericidal modes, smart charge-switching or pH-triggered activation, and biocompatible carriers to optimize efficacy while minimizing toxicity. The synthesis of mechanistic insight with material design is critical to guide rational development and clinical translation.

Cationic polymers, antimicrobial peptides, and a spectrum of nanomaterials (metal/metal oxide NPs, polymeric nanoparticles/micelles, liposomes, nanoemulsions, microneedles) constitute a promising pipeline of bioactive materials against drug-resistant bacteria and biofilms. Key advantages include multimodal mechanisms, targeted or on-demand activation, and the ability to serve as delivery vehicles to enhance antibiotic efficacy and biofilm penetration. The review highlights successful platforms with strong in vitro/in vivo efficacy, including responsive polymer–drug systems, AMP hydrogels/coatings, controlled ion-releasing Ag composites, and photothermal/photodynamic nanotherapies. Future research should focus on improving biocompatibility and selectivity, deepening mechanistic understanding in relevant infection models, simplifying designs while maintaining efficacy, conducting rigorous animal studies addressing biodistribution and immune responses, and advancing clinical translational pathways through multidisciplinary collaboration. Integration of AMPs with polymeric nanocarriers and stabilization of ultrasmall metal clusters within polymers are promising routes toward medical device coatings and wound dressings for clinical anti-infective use.

The authors identify major challenges hindering practical application: (1) Biocompatibility and selectivity—minimizing intrinsic toxicity and enhancing pathogen targeting; (2) Mechanistic understanding—moving beyond outcome metrics to detailed studies of bacteria–material interactions to inform rational design; (3) Material construction and antimicrobial efficiency—balancing simplicity, stability, and potent activity suitable for real-world use; (4) Animal experimental models—bridging in vitro efficacy with in vivo realities including metabolism, biodistribution, clearance, biodegradation, immune responses, toxicity, and inflammation; (5) Clinical translation—requiring coordinated, multidisciplinary efforts to meet regulatory, manufacturing, and clinical performance requirements.