Fluorinated hyperbranched polymers mediate spermatogonia-directed transport across the blood-testis barrier

Delivering therapeutics into seminiferous tubules remains a formidable challenge, limiting the treatment of reproductive and testis-related diseases, because the blood-testis barrier (BTB) restricts access to the luminal compartment. Here we report well-defined unimolecular fluorinated hyperbranched (Fhb) nanoparticles that can reach seminiferous tubules after systemic administration. Fhb polymers with tunable fluorine contents were synthesized via a B3 core-mediated chain-growth copper-catalyzed azide-alkyne cycloaddition polymerization, followed by terminal-group modification. Across a matched series, higher fluorine content led to markedly enhanced enrichment within seminiferous tubules following intravenous injection. Mechanistic studies indicate that this process does not rely on nonspecific BTB disruption; instead, fluorinated carriers are preferentially internalized by spermatogonia and are subsequently delivered into the tubule lumen during spermatogenesis, consistent with a conditioned-cell signaling cascade that further promotes spermatogonial uptake. As a functional demonstration, gossypol-loaded Fhb achieved complete contraception in mice after four doses, and fertility recovered after treatment cessation. These findings establish unimolecular Fhb nanoparticles as an effective platform for accessing the seminiferous-tubule compartment and enable testis-targeted therapy and reversible male contraception.