Drug–carrier molecular incompatibility as a hidden determinant of failure in cancer nanomedicine: investigation of possible solutions

Despite major advances, the clinical translation of cancer nanomedicine remains limited, with only a small proportion of formulations reaching regulatory approval. Although tumor heterogeneity, biological barriers, and patient-to-patient variability are commonly blamed, growing evidence suggests that drug-carrier molecular incompatibility is a fundamental and underrecognized cause of translational failure. In this review, molecular compatibility is defined as the thermodynamically and kinetically stable association between a therapeutic agent and its nanocarrier, governed by hydrophobic partitioning, electrostatic interactions, hydrogen bonding, miscibility, and crystallization behavior. By contrast, incompatibility refers to physicochemical mismatches that destabilize drug loading, trigger premature release, induce structural rearrangement, or alter biodistribution. Common manifestations include burst release, aggregation, chemical degradation, and loss of colloidal stability, all of which can reduce tumor accumulation, increase systemic toxicity, and weaken therapeutic efficacy. Evidence from both failed and clinically successful nanomedicines indicates that molecular compatibility, rather than carrier complexity alone, is a critical determinant of translational success. Experimental, spectroscopic, and computational methods for compatibility assessment are reviewed, together with rational design strategies including carrier selection, drug modification, surface engineering, and smart delivery systems. This review highlights compatibility as a central design and regulatory consideration in cancer nanomedicine.