Photodynamic therapy (PDT) employs lasers to activate photosensitizers, generating reactive oxygen species (ROS) for tumor cell destruction. However, the extremely short half-life of ROS and limited diffusion range restrict PDT’s therapeutic efficiency. Recent studies have shown that lysosome-targeted PDT can directly disrupt the “explosive depot” of tumor cells by triggering the release of abundant hydrolases from lysosomes. Nevertheless, existing lysosome-targeted strategies rely predominantly on a single protonation mechanism, resulting in low targeted efficiency. To enhance lysosome-targeted bursting, this study adopted a dual-mode recognition strategy, combining “hydrophobic interaction-aided fusion” with “charge-directed anchoring”. Specifically, pyropheophorbide-a (PPa) was employed as a model photosensitizer and covalently conjugated with alkyl tertiary amines of varying chain lengths (C1, C4, C8, and C12), yielding lysosome-targeted bursting photosensitizers (PPa1, PPa4, PPa8, and PPa12). Self-assembled nanoparticles (LPPa NPs) were then prepared to facilitate tumor delivery. The objective of this study was to determine the optimal chain length by evaluating the balance among ROS production efficiency, lysosomal targeted capability, and assembly stability of LPPa NPs. Notably, PPa4 NPs demonstrated superior cellular uptake, enhanced ROS generation, and effective lysosome-targeted bursting, thereby markedly improving antitumor efficacy. In summary, the dual-mode recognition strategy offered an advanced strategy for enhancing the efficiency of PDT.

Small-molecule prodrug nanoassemblies have emerged as efficient antitumor drug delivery systems. However, in the case of camptothecins-based prodrug nanoassemblies, linear aliphatic side chain modification often results in rod-shaped or irregularly shaped nanoassemblies, which are highly unfavorable for sterilization through filtration, and may cause capillary blockage upon intravenous injection. The rational design of camptothecins-based prodrug nanoassemblies remains a challenge. Herein, we propose that branched aliphatic alcohol (BAA) functionalization could fine-tune the structure-tolerance-antitumor efficacy axis of prodrug nanoassemblies. Correspondingly, four SN38-BAA prodrugs were synthesized by conjugating 7-ethyl-10-hydroxycamptothecin (SN38) with BAAs of varying lengths via a tumor redox-responsive disulfide bond, which self-assemble into uniform spherical nanoparticles. The length of BAA was found to significant impact the multiple drug delivery process, including colloidal stability, drug release profiles and pharmacokinetics. Overall, SN38-C21 NPs (SN38-11-heneicosanol nanoparticles), featuring the longest BAA, showcased multiple therapeutic advantages, ultimately culminating the optimal antitumor efficacy and tolerance. The findings underscore the potential of BAA functionalization in strengthening the therapeutic outcomes of prodrug nanoassemblies, and provide valuable insights for developing translational camptothecins-based nanomedicines.

Mitochondrial bioenergy plays a vital role in the occurrence and development of cancer. Although strategies to impede mitochondrial energy supply have been rapidly developed, the anticancer efficacy is still far from satisfactory, mainly attributed to the hybrid metabolic pathways of mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis. Herein, we construct a cancer cell membrane camouflaged nano-inhibitor, mTPPa–Sy nanoparticle (NP), which co-encapsulates OXPHOS inhibitor (mitochondrial-targeting photosensitizers: TPPa) and glycolysis inhibitor (syrosingopine (Sy)) for synergistically blocking the two different energy pathways. The mTPPa–Sy NPs exhibit precision tumor-targeting due to the high affinity between the biomimic membrane and the homotypic cancer cells. Under laser irradiation, the mitochondrial-targeting TPPa, which is synthesized by conjugating pyropheophorbide a (PPa) with triphenylphosphin, produces excessive reactive oxygen species (ROS) and further disrupts the OXPHOS. Interestingly, OXPHOS inhibition reduces O₂ consumption and improves ROS production, further constructing a closed-loop OXPHOS inhibition system. Moreover, TPPa-initiated OXPHOS inhibition in combination with the Sy-triggered glycolysis inhibition results in lethal energy depletion, significantly suppressing tumor growth even after a single treatment. Our findings highlight the necessity and effectiveness of synergetic lethal energy depletion, providing a prospective strategy for efficient cancer therapy.