Engineering poly(alkyl cyanoacrylate) nanoparticles via in situ emulsion polymerization: From synthesis to clinical perspectives.

Poly(alkyl cyanoacrylate) (PACA) nanoparticles (NPs) have been investigated for over four decades as biodegradable nanocarriers for drug delivery. Prepared by in situ anionic emulsion polymerization of alkyl cyanoacrylate monomers in the presence of polymer stabilizers, PACA NPs consist of a PACA matrix core surrounded by a stabilizer shell. The alkyl side chain is a critical design parameter governing polymerization kinetics, degradation rate - through competing hydrolytic erosion and enzymatic side-chain cleavage - and drug release. PACA NPs associate a broad range of active pharmaceutical ingredients via entrapment during polymerization or surface adsorption. Preclinical studies have demonstrated their therapeutic potential across oncology, central nervous system disorders, infectious diseases, and oral peptide delivery. Their capacity to reverse multidrug resistance - through a dual mechanism combining plasma membrane adsorption and ion pair formation between polycyanoacrylic acid and cationic drugs such as doxorubicin - provided the scientific rationale for the most advanced clinical program: doxorubicin-loaded poly(isohexyl cyanoacrylate) NPs in hepatocellular carcinoma. This experience highlighted both the translational potential and the persistent challenges of PACA nanomedicines, including route-dependent complement activation (CARPA), the importance of pharmaceutical-grade scale-up, and the risk of being outpaced by evolving standards of care. This review critically analyses PACA NPs prepared by in situ emulsion polymerization - from monomer structure and polymerization mechanisms to physicochemical characterization, drug association, biological performance, degradation, toxicology, and clinical translation - bridging fundamental polymer chemistry and translational nanomedicine.