Hexylaminolevulinic acid in precision medicine: A review of advances in drug delivery and combination therapeutics

Hexylaminoacetylpropionic acid (HAL), a third-generation photosensitizer prodrug, exhibits targeted accumulation within tumor tissues and microbial biofilms. This review outlines advances in HAL-based drug delivery systems and their expanding use in various diseases, including oncology, antimicrobial therapy, and dermatologic diseases. Clinically, HAL has proven instrumental in enhancing diagnostic accuracy for bladder cancer by facilitating more complete surgical resections, while also demonstrating therapeutic efficacy against actinic keratosis and cervical intraepithelial neoplasia. These clinical advantages are complemented by novel nanocarrier systems that optimize drug delivery that improve patient tolerability. Recent findings point to an underappreciated the interplay between HAL-induced metabolic changes in tumours and anti-tumour immune responses, in which HAL-induced metabolic changes in tumours and anti-tumour immune responses, in which HAL-induced induces cell apoptosis through mitochondrial membrane permeabilization and the nuclear translocation of AIF, and enhances the efficacy of immune checkpoint blockade of key regulatory proteins reshape the tumour microenvironment and enhance immunogenicity. Thus, HAL is a candidate for combination with immune checkpoint inhibitors. However, challenges such as shallow light penetration (<2 mm) and the need for long-term safety validation limit its broader clinical utility. We propose three convergent strategies to address these limitations: (i) reactive oxygen species-responsive nanocarriers for targeted delivery in hypoxic environments, (ii) biomarker-guided combinatorial regimens, and (iii) data-driven treatment personalisation using patient-specific biomarkers. Together, these advances establish a translational framework for HAL as a platform in next-generation metabolism-targeted photomedicine.