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Abstract This review focuses on nanoparticle (NP)–based cancer therapies, which have demonstrated considerable potential but whose clinical effectiveness is hindered by multiple biological barriers, including rapid systemic clearance, limited tumor accumulation, formation of the protein corona, immune recognition and poor tumor cell interaction. Although PEGylation emerged as a gold-standard method to mitigate these challenges through reduced opsonization and prolonged systemic circulation, significant drawbacks such as steric hindrance, diminished cellular uptake, and immunogenicity (anti-PEG antibodies, accelerated blood clearance) necessitate exploring advanced alternatives. This review critically examines the limitations of PEGylation and evaluates cutting-edge NP surface modulation strategies designed to enhance tumor targeting and therapeutic efficacy. Since the fundamental barrier to effective tumor delivery originates from non-specific interactions, we broaden the perspective on these interactions and introduce diverse approaches aimed at minimizing them. Specifically, we highlight studies exploiting the chemical identity of nanoparticles through control of PEG chain length and surface density, reduction of non-specific interactions to improve active targeting efficiency, the influence and functional utilization of PEG terminal groups, and the potential of branched polymers and surface topology. Furthermore, stimuli-responsive PEG shedding strategies (pH-sensitive, enzyme-responsive, light-triggered) are discussed for their ability to dynamically resolve the “PEG dilemma” by balancing stealth properties with effective cellular interactions. Finally, we introduce alternative hydrophilic polymer coatings overcoming immunogenicity of PEG. By systematically addressing how advanced NP surface engineering influences pharmacokinetics, protein corona dynamics, tumor microenvironment (TME) interactions, and immune responses, this review outlines key design principles to propel the next generation of highly effective cancer nanomedicines from preclinical promise to clinical reality. Graphical abstract
Taghavimandi et al. (Mon,) studied this question.