Overcoming cholesterol-induced pulmonary toxicity: plant sterols and natural saponins as bioactive alternatives in inhalable liposomes for active carrier-mediated synergistic therapy.

Exogenous cholesterol is routinely incorporated into inhalable liposomes to enhance membrane stability under nebulization-induced shear stress. However, excessive cholesterol deposition may trigger lipid overload in alveolar macrophages, activate the NLRP3 inflammasome, and induce pulmonary immunotoxicity, thereby severely restricting the clinical translation of such liposomal formulations. Given their ethnopharmacological relevance and structural homology, natural plant sterols and bioactive saponins derived from medicinal herbs have emerged as promising substitutes for cholesterol. These two classes of phytochemicals not only stabilize lipid bilayers by inducing a compact liquid-ordered phase but also exert intrinsic pharmacological activities, including promoting lipid efflux, suppressing inflammatory responses, and maintaining redox homeostasis, thus enabling the transformation of liposomes from passive carriers into active synergistic delivery systems. This review systematically summarizes the recent advances in plant sterols and saponins as cholesterol alternatives in inhalable liposomes, highlights their applications in chronic airway inflammation, reversal of multidrug resistance in lung cancer, and nucleic acid inhalation delivery, and discusses the key engineering challenges and translational prospects. It aims to provide an ethnopharmacology-based formulation strategy for developing safe, multi-target, and synergistic pulmonary nanomedicines.