Smart nanoparticle delivery systems for curcumin: a targeted strategy to enhance anticancer efficacy and bioavailability.

Curcumin, a natural polyphenol derived from Curcuma longa, exhibits potent multimodal anticancer activity by modulating critical oncogenic pathways (e.g., NF-κB, STAT3, PI3K/Akt/mTOR), inducing apoptosis, suppressing angiogenesis, and reversing multidrug resistance (MDR). However, its clinical translation is severely hindered by poor aqueous solubility, rapid metabolism, and negligible oral bioavailability (typically <1% in serum), which result in subtherapeutic concentrations at tumor sites. Smart nanoparticle delivery systems have emerged as a transformative strategy to overcome these limitations, enabling enhanced solubility, controlled release, and targeted accumulation in tumors. This review comprehensively summarizes the advancements in curcumin-loaded nanocarriers, including polymeric nanoparticles (e.g., PLGA, chitosan), lipid-based systems (e.g., liposomes, NLCs), inorganic nanoparticles (e.g., mesoporous silica, gold nanoparticles), and stimuli-responsive platforms (pH-, redox-, enzyme-sensitive). These nanosystems leverage passive targeting via the enhanced permeability and retention (EPR) effect and active targeting through ligand conjugation (e.g., folate, transferrin, hyaluronic acid), significantly improving tumor-specific delivery and curcumin's bioavailability-exemplified by a 178-fold increase in plasma AUC in healthy human volunteers following oral administration of the co-grinding formulation CUMINUP60® compared to standard crystalline curcumin. Preclinical and clinical studies demonstrate that nanoformulated curcumin synergizes with conventional chemo/radiotherapy, sensitizes resistant cancers, and modulates the immunosuppressive tumor microenvironment. For instance, Phase I/II trials indicate that formulations like nanomicellar curcumin (Sinacurcumin®) can modulate inflammatory cytokines, while liposomal variants (Lipocur™) have shown target engagement in metastatic cancers, albeit with the need for dose optimization. Hybrid nanocarriers co-delivering curcumin with chemotherapeutics or siRNA further augment therapeutic outcomes in models of colorectal, breast, pancreatic, and glioblastoma cancers. Despite these progresses, the gap between preclinical success and clinical translation remains significant. This review critically analyzes the barriers impeding commercialization, specifically highlighting the heterogeneity of the EPR effect, the lack of scalable GMP-compliant manufacturing for complex nanocarriers, and the regulatory hurdles regarding long-term biocompatibility and safety assessments.