Polymeric nanoparticle platforms for ibrutinib delivery: tackling solubility, CYP3A4-mediated metabolism, and resistance to facilitate BTK-targeted therapy in solid tumours

Because of its poor aqueous solubility, low oral bioavailability, extensive cytochrome P450 3A4 (CYP3A4)-mediated metabolism, and acquired resistance, ibrutinib, a first-in-class covalent Bruton's tyrosine kinase (BTK) inhibitor, has shown limited efficacy in solid tumors despite revolutionizing the treatment of B-cell malignancies. Despite growing evidence linking BTK and 65-kDa Bruton's tyrosine kinase isoform (p65BTK) signaling to nuclear factor kappa-B (NF-κB) and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT)-mediated tumor progression, immune evasion, and therapeutic resistance, these limitations have limited its therapeutic repurposing in breast, lung, colorectal cancer (CRC), and glioblastoma. While acknowledging the variable clinical applicability of the enhanced permeability and retention (EPR) effect in human tumors, this review critically assesses recent developments in polymeric nanoparticle (PNP)-based delivery systems for Ibrutinib, highlighting their potential to improve drug stability, enable sustained and stimuli-responsive release, enhance tumor accumulation, and facilitate active ligand-mediated targeting. A thorough literature search of PubMed, Scopus, Web of Science, ScienceDirect, and Google Scholar found studies published between 2010 and 2026. Preclinical data collectively show that PNPs improve antitumor efficacy, alter the tumor microenvironment, inhibit drug resistance and cancer stemness, lower systemic toxicity, and offer a promising platform for the clinical translation of precision BTK-targeted nanomedicine in solid tumors.