Plasma Carrier Proteins as Supramolecular Nanovectors for Cancer Therapy: The Trojan Horse Approach

Conventional chemotherapeutics often suffer from poor aqueous solubility, short circulation half-lives, lack of tumor selectivity, and present dose-limiting systemic toxicity. This perspective examines the Trojan Horse Approach (THA), in which plasma carrier proteins (PCPs) are exploited as discrete, non-covalent supramolecular hosts for chemotherapeutic agents, and discusses its potential to overcome the limitations of both free drugs and conventional protein nanoparticles. Two principal strategies for assembling ex vivo drug–protein complexes are discussed: (i) molecular recognition, in which drugs occupy native ligand-binding pockets, and (ii) molecular anchoring, in which drugs are conjugated to high-affinity anchor ligands. The perspective critically assesses the current state of the art, distinguishes different levels of experimental validation, and discusses the major limitations and barriers to clinical translation. Structural, biochemical, and pharmacological evidence is examined for human serum albumin, transferrin, transthyretin, alpha-1-acid glycoprotein, alpha-fetoprotein, lactoferrin, and other plasma proteins. When appropriately designed and validated, protein-based complexes may preserve the native protein structure while conferring improved drug solubility, protection from premature metabolism, prolonged systemic circulation and enhanced tumor accumulation via combined passive and active targeting. PCPs represent a versatile and underexploited toolbox for cancer drug delivery. Expanding the repertoire of protein carriers, applying in silico rational design to guide the selection and optimization of drug–protein complexes, and exploring the use of patient-derived autologous proteins may open new opportunities for more effective and personalized therapies.