Protocatechuic Acid (3,4‐Dihydroxybenzoic Acid)‐Loaded Polymeric Nanoparticles Empowering Multimodal Cancer Therapy With Targeted Delivery and Translational Potential

ABSTRACT Cancer treatment faces critical challenges, that is, tumor heterogeneity, multidrug resistance and severe toxicity from traditional therapies. Protocatechuic acid (PCA) (3,4‐dihydroxybenzoic acid), a natural phenolic compound, has multi‐targeted anticancer effects by regulating apoptosis, the immune response, angiogenesis, metastasis, and oxidative stress. However, clinical use of PCA is limited by its rapid metabolism, poor water solubility and chemical instability. Advances in polymer‐based drug delivery systems, including biodegradable nanoparticles, hydrogels, and metal–organic frameworks, have provided solutions by improving PCA's stability, bioavailability, and tumor‐targeting ability through controlled, stimuli‐responsive release. Preclinical studies have shown that PCA‐loaded polymeric nanocarriers exhibit potent anticancer activity in breast, colorectal, lung, prostate, and cervical cancers. These platforms enhance therapeutic efficacy, reverse chemoresistance and reduce off‐target toxicity, supporting multi‐modal treatment. Sustainable methods for large‐scale PCA production, such as green extraction and enzymatic synthesis, further enhance translational potential. Although early studies show promise, PCA nanoparticle formulas need improvement and testing in humans. This review connects PCA with polymer design, showing recent advances in targeting tumors and overcoming barriers. PCA‐loaded nanoparticles bring safer, more effective cancer treatments closer to reality.