AI and Nanodelivery Systems Engineer Host-Defense Peptides to Overcome Biofilms and Antimicrobial Resistance

The escalating global crisis of Antimicrobial Resistance (AMR) poses a severe threat to public health, rendering conventional antibiotics increasingly ineffective against bacterial infections. A critical challenge is the formation of biofilms, complex microbial communities that shield bacteria from antibiotics and host immune responses. Current treatments often fail to penetrate these protective matrices, leading to persistent and recurrent infections. Host-defense peptides (HDPs), naturally occurring broad-spectrum antimicrobials, offer a promising alternative due to their diverse mechanisms of action and lower propensity for resistance development, but their therapeutic application is limited by stability, toxicity, and delivery challenges.

This review synthesizes current advancements in engineering host-defense peptides (HDPs) using artificial intelligence (AI) and nanodelivery systems to combat antimicrobial resistance (AMR) and biofilms. It explores how AI algorithms, including machine learning and deep learning models, are employed for the rational design and optimization of HDP sequences, predicting their antimicrobial activity, toxicity profiles, and stability. Concurrently, the paper examines various nanocarriers, such as liposomes, nanoparticles, micelles, and hydrogels, designed to improve HDP stability, bioavailability, and targeted delivery to infection sites, particularly within biofilms.

The review identifies that AI-driven approaches significantly accelerate the discovery and optimization of novel host-defense peptides (HDPs) by predicting their structure-activity relationships and identifying sequences with enhanced antimicrobial potency and reduced cytotoxicity. These computational methods can screen vast chemical spaces, overcoming the limitations of traditional, laborious screening methods. Furthermore, the integration of nanodelivery systems is shown to overcome key limitations of native HDPs, such as rapid enzymatic degradation, systemic toxicity, and poor penetration into biofilms. Nanocarriers facilitate sustained release and targeted accumulation of HDPs at infection sites, leading to improved therapeutic indices. This dual approach enhances HDP stability, prolongs their half-life, and enables localized, high-concentration delivery, which is crucial for overcoming bacterial resistance mechanisms and biofilm matrices. > The combination of AI-guided design and nanocarrier encapsulation represents a powerful strategy to develop next-generation antimicrobials capable of penetrating and disrupting mature biofilms and combating multidrug-resistant (MDR) pathogens. The synergistic application of AI and nanotechnologies provides a robust platform for engineering HDPs with superior efficacy and safety profiles.