CINNAMALDEHYDE NANOPARTICLES AND THEIR ANTI-CANCER MECHANISM: A COMPREHENSIVE REVIEW

Abstract

Cinnamaldehyde (CA), the principal phenylpropanoid of Cinnamomum species, exhibits multifaceted anticancer activity but is constrained by volatility, poor aqueous solubility, and rapid biotransformation. Nanoparticle formulations (CNNPs) including solid lipid nanoparticles, chitosan‑based hybrids, and mesoporous composites   address these liabilities by improving encapsulation efficiency, physicochemical stability, controlled release, and tumor‑selective delivery via ligand mediation (e.g., folate or transferrin receptors). Mechanistically, CNNPs elevate reactive oxygen species (ROS), precipitating mitochondrial membrane potential loss (ΔΨm), cytochrome‑c efflux, and caspase‑3/9 activation, while concurrently attenuating pro‑survival signaling through PI3K/Akt–mTOR and NF‑κB pathways and enforcing G0/G1 or G2/M cell‑cycle arrest with p53/p21 engagement. Mounting evidence positions autophagy as a central determinant of therapeutic outcome: CA triggers ER‑stress (PERK–CHOP) and epigenetic remodeling that up‑regulates Beclin‑1 and ATG family members, drives LC3‑II accumulation, and   under defined conditions   promotes autophagic cell death. Because autophagy is intrinsically context dependent and can be cytoprotective or cytotoxic, nanoparticle design (size, surface charge, ligand density, endosomal escape features), exposure kinetics, and tumor genotype collectively bias directionality. This review synthesizes 2020–2025 advances in CIN‑NP engineering and cancer biology with an autophagy‑first lens, integrates crosstalk among ROS, mitochondrial dysfunction, and mTOR signaling, and delineates best practices for verifying autophagic flux. Key translational challenges   including nanotoxicity, off‑target biodistribution (e.g., hepatic uptake with folate targeting), endosomal trapping, manufacturing scalability, and assay interference risks   are critically appraised. Finally, a forward agenda is proposed that links rational CIN‑NP design to rigorous mechanistic validation and in‑vivo pharmacology to accelerate clinically meaningful, autophagy‑informed nanotherapeutics