Protein-based nanocarriers in the management of hard-to-treat solid tumours.

Despite a steady decline in overall cancer mortality, the survival rates of certain hard-to-treat cancers of the lung, liver, oesophagus, pancreas, and brain remain strikingly low. A key unmet need in this field is the development of effective systemic therapies, for which nanotechnology offers promising solutions. While liposomal formulations have dominated the clinical landscape in oncology, protein-based nanocarriers (NCs) have emerged as biocompatible and biodegradable alternatives with intrinsic biological activity. The most notable example, nanoparticle albumin-bound (nab-)paclitaxel, has been in clinical use since 2005, however the development of new protein-based NCs has since largely stagnated for various reasons. For instance, while albumin has been employed in NC formulation since 1978, its intracellular trafficking remains poorly understood, and the proposed mechanism of tumour uptake based on glycoprotein 60-mediated transcytosis is not supported by adequate evidence. Beyond albumin, twelve other proteins have been explored for NC formulation in hard-to-treat cancers, yet none have progressed to clinical trials due to challenges with reproducibly and immunogenicity. Furthermore, conventional NC fabrication methods such as desolvation and homogenisation face stability and biocompatibility issues, limiting clinical translation. Additional hurdles include suboptimal choice of drug cargo, insufficient tumour targeting, and inadequate preclinical biological validation. To address these issues, this review critically evaluates the current landscape of protein-based NCs (including all multi-protein assemblies in the nature of nab-paclitaxel but excluding antibody-drug conjugates and virus-like nanoparticles) in the context of hard-to-treat cancers and highlights practical strategies to overcome their limitations with the goal of advancing these NCs towards clinical implementation.