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Life sciences · Journal article
Frontiers in Pharmacology · October 9, 2026
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Background Carrier-free self-assembled nanodrugs use therapeutic or bioactive molecules as principal structural components. Their architectures have diversified rapidly, but how molecular design relates to resistance evidence and further development remains unclear. Objective To map molecular architecture, drug-resistance evidence, and translation-relevant reporting in carrier-free anticancer nanodrugs. Methods We conducted a PRISMA-ScR systematic scoping review and evidence map integrated with bibliometric analysis and structured appraisal of key resistance studies. PubMed, Europe PMC, Scopus, and Web of Science Core Collection (WoSCC) were searched in August 2026. WoSCC records (n = 863) characterized publication and intellectual structure, Scopus records (n = 840) assessed coverage, and 526 eligible articles formed the evidence map. Architecture was classified in 481 original studies, resistance evidence in 160 records, and 19 translation-relevant domains in 147 full-text studies. All 43 Tier 1/2 studies underwent full-report appraisal. Results Covalent prodrug/conjugate assemblies (n = 187) and noncovalent multi-active co-assemblies (n = 182) predominated. Of 160 resistance-related records, 28 used established resistant models (Tier 1), whereas 15 provided mechanism-aligned sensitization evidence without resistant-model confirmation (Tier 2). Architecture was not clearly associated with Tier one versus Tier 2 classification in exploratory analysis (Cramér’s V = 0.394, Holm-adjusted P = 0.666). In the 147-study full-text subset, batch consistency and experimental scalability were each reported in three studies and long-term toxicity in four. Seven studies met the composite human-related evidence domain, but only one involved direct clinical administration (1/147, 0.7%). After excluding incomplete 2026 data, the latest-versus-earliest difference in reporting completeness was 1.40 domains (95% CI, −0.49–3.25), providing no clear evidence of sustained temporal improvement. Conclusion Carrier-free anticancer nanodrugs have diversified rapidly, but evidence supporting resistance and further development has not matured in parallel. By separating resistance mechanism from evidentiary strength and distinguishing resistant-model validation from mechanism-aligned sensitization, this review establishes clearer boundaries for resistance claims and identifies manufacturing reproducibility, long-term safety, and direct clinical evaluation as major evidence gaps. The resulting framework provides a practical basis for aligning molecular design with claim-specific pharmacology and development-oriented evidence generation.