Inhaled multilevel size-tunable, charge-reversible and mucus-traversing composite microspheres as trojan horse: Enhancing lung deposition and tumor penetration

Dry powder inhalation represents a promising approach for the treatment of lung cancer, offering several advantages such as enhanced targeting, improved bioavailability, and reduced toxicity. However, traditional dry powder formulations suffer from limitations, notably low pulmonary delivery efficiency and inadequate penetration into tumor tissues, thereby limiting their therapeutic efficacy. In response to these challenges, we have developed an innovative trojan horse strategy, harnessing an inhalable nanoparticle-in-microsphere system characterized by tunable size, reversible charge, and mucus-penetrating capabilities. The inhalable nanoparticle-in-microsphere system exhibit stable structural properties, excellent environmental responsiveness and high biocompatibility. More importantly, the therapeutic effect of MTX@PAMAM@HA@Gel (MPHG) was demonstrated in vitro and in vivo. This system offers improved pulmonary delivery efficiency, enhanced drug retention within tumor tissues, and effective penetration, thus representing a promising strategy in lung cancer treatment.