Beyond Uptake in Cancer Lipid Nanomedicines: Linking Tumour Access, Intracellular Fate, and Molecular Action

Clinical translation of lipid nanomedicines in oncology is limited by biological barriers and by an interpretive challenge: tumour accumulation and cellular uptake are often used as proxies for delivery even when pharmacologically competent cargo, meaning cargo capable of producing its intended molecular effect, has not reached the relevant cell and intracellular machinery required for its intended molecular action. This narrative review synthesises mechanistic and translational evidence across liposomes, ionisable lipid nanoparticles (LNPs), cationic lipid systems, solid lipid platforms, and lipid–polymer hybrids, focusing on systemically administered formulations for solid tumours. The review follows the delivery sequence from tumour access and cell-type allocation (distribution of tumour-accessed material among tumour-associated cell populations) through internalisation, intracellular sorting, endosomal escape where required, cargo release or bioconversion, and cargo-specific molecular action. Upstream gains can fail downstream through sequestration, recycling, lysosomal trapping, inefficient escape, delayed release, uncertain cell allocation, or toxicity. Because delivery requirements are cargo-dependent, nucleic-acid LNPs generally require cytosolic access and intracellular machinery, whereas liposomal small molecules may depend more on timed release, bioconversion, and active-drug exposure. Strong mechanistic inference therefore requires readouts that distinguish carrier from cargo, resolve cellular and subcellular location, and demonstrate cargo-specific pharmacology. The central design implication is to identify the dominant biological bottleneck and prioritise safe, cell-specific pharmacological output rather than uptake intensity alone.