Photoreceptor-targeted engineered exosomes encapsulating black phosphorus quantum dots for alleviating photoreceptor degeneration

Photoreceptor degeneration is a major cause of irreversible visual impairment worldwide, most notably in retinitis pigmentosa (RP). Here, we developed a dual-targeted therapeutic nanoplatform by loading black phosphorus quantum dots (BPQDs) into human dental pulp mesenchymal stem cell-derived exosomes (hDPSC-Exos) and surface-modifying with cell-penetrating peptide transactivated transcription (TAT) and photoreceptor-specific peptide MH42, namely TAT/MH42-engineered black phosphorus quantum dot-loaded exosomes (M/T-BPQD@Exos). M/T-BPQD@Exos showed typical exosomal morphology and good uniformity. In vitro, M/T-BPQD@Exos effectively protected 661 W photoreceptor cells against N-methyl-N-nitrosourea (MNU) injury. In vivo, M/T-BPQD@Exos specifically accumulated in the outer nuclear layer (ONL) and significantly preserved retinal structure and visual function in MNU-induced photoreceptor degeneration rats. Biosafety assessment confirmed no obvious systemic toxicity and inflammation. Mechanistically, M/T-BPQD@Exos alleviated calcium overload, maintained mitochondrial integrity, and suppressed mitochondrial apoptosis by regulating Bcl-2, Bax, and cleaved caspase-3. This study provides a safe and precise strategy for photoreceptor protection in retinal degenerative diseases.