Advancements in hydroxypropyl methylcellulose-polyethylene glycol hybrid excipients and their nanoformulations for controlled and ligand-directed biologic delivery.

The delivery of biologic drugs presents unique formulation challenges due to their high molecular weight, instability in physiological environments, and complex pharmacokinetics. Hybrid excipient systems, particularly those combining hydroxypropyl methylcellulose (HPMC) and polyethylene glycol (PEG), offer a versatile platform for addressing these issues. Hydroxypropyl methylcellulose (HPMC), a semi-synthetic polymer, is widely recognized for its gel-forming ability, biocompatibility, and capacity to enable sustained drug release. Polyethylene glycol (PEG), a hydrophilic polyether, is commonly employed to enhance solubility, reduce protein aggregation, and improve mucosal permeability. This review presents a focused analysis of HPMC-PEG-based different formulation strategies that support controlled, sustained, and site-specific delivery of biologics across various routes including oral, nasal, ocular, parenteral, and pulmonary. Furthermore, the review discusses mechanistic insights, PEG-related immunogenicity concerns, and regulatory considerations that are critical for clinical translation. Key aspects such as formulation strategies, physicochemical properties, in vitro and in vivo performance, and targeting capabilities are discussed. Additionally, the challenges associated with the scale-up, regulatory approval, and potential toxicity of these hybrid systems are explored. By integrating physicochemical behavior with route-specific delivery outcomes, this review provides a consolidated, application-oriented perspective that bridges formulation science with therapeutic advancement in biologics. This distinguishes it from prior work and offers practical guidance for excipient scientists and pharmaceutical developers. This review also provides insights into the future directions and applications of HPMC-PEG hybrid excipients and the developed nanoformulations in personalized medicine and sustained-release drug product.