ABSTRACT Peripheral arterial disease (PAD) is a severe impairment of arterial vessels resulting in obstruction of normal blood flow in the legs, leading to acute or chronic lower limb ischemia and subsequently high morbidity and mortality rates. Common treatments for PAD, such as medications and surgical revascularization, have several limitations. For instance, medications used to lower cholesterol, reduce high blood pressure, control blood sugar, prevent blood clots, and relieve symptoms like leg pains may delay onset. Still, they cannot treat the established disease directly and often cause side effects, including bleeding, headache, and diarrhea. Meanwhile, many elderly PAD patients cannot undergo surgical options. Therefore, it is vital to develop an alternative therapy to treat PAD. Our long-term goal is to develop novel degradable dual-modal imaging nanoparticles (DINPs) to precisely deliver therapeutic reagents that provide cell protection and facilitate the formation of blood vessels de novo at ischemic sites while allowing detection of the NP location and monitoring of their therapeutic effectiveness for PAD treatment. We have three specific aims: (1) To synthesize, characterize and optimize our biodegradable dual-modal fluorescent/photoacoustic elastomers named biodegradable photoluminescent polymers-aniline tetramers (BPLPAT), (2) To formulate and analyze DINPs made of optimized BPLPATs and loaded with therapeutic reagents for facilitating cell protection and angiogenesis, and (3) To evaluate the effectiveness of DINPs to treat PAD in vivo using animal models. Innovative aspects of this research are i) the use of our novel BPLPAT material allowing both fluorescent and deep-tissue photoacoustic imaging opportunities to detect the in vivo distribution of these NPs and evaluate their degradation assessment; ii) development of DINPs based on recent advances in nanotechnology and tissue engineering providing a unique strategy to deliver new therapeutic agents to the ischemic site in order to enhance cellular protection and promote angiogenesis in situ under hypoxic conditions such as ischemic tissues. The rigor of prior research and scientific feasibility of our developed DINPs are well-established as we have already demonstrated (1) their detectability via both fluorescence and photoacoustic imaging, (2) the retention of DINPs loaded with therapeutic agents at the ischemic zones, (3) the release of therapeutic compounds in a sustained manner, and (4) their capacity to provide cell protection and promote angiogenesis to recover blood perfusion after ischemia. The success of our research will provide a novel therapy for the effective treatment of PAD.